Heterocyclic amide compound

ABSTRACT

wherein each symbol is as described in the DESCRIPTION, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a heterocyclic amide compound that mayhave a prolyl-tRNA synthetase (PRS) inhibitory action and is expected tobe useful as a prophylactic or therapeutic agent for PRS associateddiseases and the like including cancer.

BACKGROUND OF THE INVENTION

As a compound having a PRS inhibitory activity, febrifugine derivativesrepresented by halofuginone can be mentioned. They were known asantimalarial drugs in the past and application thereof to cancer,fibrosis, inflammatory diseases and the like has been expected in recentyears (non-patent documents 1, 2). As for halofuginone, for example, ananti-cancer action against osteosarcoma and colorectal cancer has beenreported (non-patent documents 3, 4). PRS is one of the aminoacyl tRNAsynthases, involved in the synthesis of proteins, and is suggested to berelated to cancer (non-patent document 5).

DOCUMENT LIST Non-Patent Documents

-   non-patent document 1: Jain V et al., Structure 23, 819-829, May 5,    2015-   non-patent document 2: Keller T L et al., Nat Chem Biol. 2012 Feb.    12; 8(3):311-7-   non-patent document 3: Lamora A et al., Oncotarget. 2015 Jun. 10;    6(16):14413-27-   non-patent document 4: Chen G Q et al., Oncotarget. 2015 Sep. 15;    6(27):24148-62-   non-patent document 5: Kim S et al., Nat Rev Cancer. 2011 Sep. 23;    11(10):708-18

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a novel heterocyclicamide compound that may have a PRS inhibitory action and is expected tobe useful as a prophylactic or therapeutic agent for PRS associateddiseases and the like including cancer, and a medicament containingsame.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problems and found that a compound representedby the following formula (I) may have a superior PRS inhibitory action,which resulted in the completion of the present invention.

Therefore, the present invention provides the following.

[1] A compound represented by the following formula (I):

wherein a group represented by

is an optionally substituted aromatic ring group;

R¹ is a hydrogen atom, a halogen atom, a cyano group, an optionallysubstituted alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted amino group, or an optionallysubstituted hydroxy group;

X¹ is CR² or a nitrogen atom;

X² is CR³ or a nitrogen atom;

R² and R³ are each independently a hydrogen atom, a halogen atom, or anoptionally substituted alkyl group;

X³ is CR⁴R⁵ or NR⁶, X⁴ is CR⁷R₈, X⁵ is CR⁹R¹⁰ or an oxygen atom;

R⁴ is a hydrogen atom, a cyano group, an optionally substitutedhydrocarbon group, or an optionally substituted heterocyclic group;

R⁵ is a cyano group, an optionally substituted hydrocarbon group, or anoptionally substituted heterocyclic group;

R⁴ and R⁵ are optionally bonded to each other to form, together with theadjacent carbon atom, an optionally further substituted ring; and

R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently a hydrogen atom, anoptionally substituted hydrocarbon group, or an optionally substitutedheterocyclic group,

or a salt thereof (sometimes to be abbreviated as “compound (I)” in thepresent specification).

[2] The compound of [1] wherein the group represented by

is a C₆₋₁₄ aryl group, a 5- or 6-membered monocyclic aromaticheterocyclic group or a 8 to 14-membered fused polycyclic aromaticheterocyclic group, each of which is optionally substituted by 1 to 5substituents selected from(1) a halogen atom,(2) a cyano group,(3) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms,(4) a C₆₋₁₄ aryl group,(5) a C₁₋₆ alkoxy group and(6) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 3 substituents selected from

(i) a cyano group,

(ii) a halogen atom,

(iii) a C₁₋₁₂ alkyl group optionally substituted by 1 to 6 substituentsselected from (a) a halogen atom, (b) a cyano group, (c) a hydroxygroup, (d) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3halogen atoms, (e) a C₁₋₆ alkoxy group optionally substituted by a C₁₋₆alkoxy group, (f) a C₆₋₁₄ aryl group, (g) a C₁₋₆ alkoxy-carbonyl group,(h) a carbamoyl group, (i) a C₁₋₆ alkyl-sulfonyl group, (j) a 3- to14-membered non-aromatic heterocyclic group optionally substituted by 1to 3 C₁₋₆ alkyl groups and (k) a 5- to 14-membered aromatic heterocyclicgroup,

(iv) a C₃₋₁₀ cycloalkyl group,

(v) a 3- to 14-membered non-aromatic heterocyclic group,

(vi) a C₁₋₆ alkoxy-carbonyl and

(vii) an oxo group;

-   -   R¹ is (1) a hydrogen atom, (2) a halogen atom, (3) an alkyl        group optionally substituted by 1 to 3 substituents selected        from a halogen atom, a cyano group, a hydroxy group and a C₁₋₆        alkoxy group, (4) an alkynyl group optionally substituted by a        hydroxy group, or (5) a hydroxy group optionally substituted by        a C₁₋₆ alkyl group;    -   X¹ is CR²a (R^(2a) is a hydrogen atom or a halogen atom) or a        nitrogen atom;    -   X² is CR^(3a) (R^(3a) is a hydrogen atom or a halogen atom) or a        nitrogen atom;    -   X³ is CR^(4b)R^(5b) (R^(4b) and R^(5b) are each independently a        cyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or a C₃₋₁₀        cycloalkyl group);    -   X⁴ is CR^(7b)R^(7b) (R^(7b) and R^(8b) are each        independently (1) a hydrogen atom or (2) a C₁₋₆ alkyl group        optionally substituted by 1 to 3 substituents selected from a        cyano group, a hydroxy group and a C₁₋₆ alkoxy group); and    -   X⁵ is CR^(9b)R^(10b) (R^(9b) and R^(10b) are each independently        a hydrogen atom or a C₁₋₆ alkyl group);        or a salt thereof.        [3] A medicament comprising the compound of [1] or a salt        thereof.        [4] The medicament of [3] which is a PRS inhibitor.        [5] The medicament of [3] which is a prophylactic or therapeutic        agent for cancer.        [6] The compound of [1] or a salt thereof which is used for the        prophylaxis or treatment of cancer.        [7] A method for inhibiting PRS in a mammal, comprising        administering an effective amount of the compound of [1] or a        salt thereof to the mammal.        [8] A method for preventing or treating cancer in a mammal,        comprising administering an effective amount of the compound of        [1] or a salt thereof to the mammal.        [9] Use of the compound of [1] or a salt thereof for producing a        prophylactic or therapeutic agent for cancer.

Effect of the Invention

According to the present invention, a heterocyclic amide compound thatmay have a PRS inhibitory action and is expected to be useful as aprophylactic or therapeutic agent for PRS associated diseases and thelike including cancer, and a medicament containing same are provided.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “C₁₋₁₂ alkyl group”include the above-mentioned “C₁₋₆ alkyl group”, heptyl, octyl, nonyl,decyl, undecyl, dodecyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms.

Specific examples thereof include methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl,2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms.

Specific examples thereof include methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy andhexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, l-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[substituent group A](1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include “an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl)

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocycle” include anaromatic heterocycle and a non-aromatic heterocycle, each containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic(preferably bi or tricyclic) aromatic heterocycles such asbenzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,benzothiazole, benzisothiazole, benzotriazole, imidazopyridine,thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine,thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine,pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole,isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, phenothiazine,phenoxazine and the like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepane, diazepane, azepine, azocane, diazocane, oxepane and the like;and

9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-3-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include a “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

In the present specification, examples of the “aromatic ring group” ofthe “optionally substituted aromatic ring group” include theabove-mentioned “C₆₋₁₄ aryl group” and “aromatic heterocyclic group”,and examples of the substituent thereof include the above-mentioned“substituent”.

In the present specification, examples of the “ring” of the “optionallyfurther substituted ring” include the above-mentioned “hydrocarbon ring”and the above-mentioned “heterocycle”, and examples of the substituentthereof include the above-mentioned “substituent”.

The definition of each symbol in the formula (I) is explained below.

The group represented by

(hereinafter sometimes to be referred to as “ring A group” forsimplification) is an optionally substituted aromatic ring group.

The “aromatic ring group” of the “optionally substituted aromatic ringgroup” for ring A group is preferably

a C₆₋₁₄ aryl group (e.g., phenyl, naphthyl) or

an aromatic heterocyclic group (thienyl, benzothienyl), more preferably,

a C₆₋₁₄ aryl group (e.g., phenyl, naphthyl),

a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,thienyl) or

a 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic)aromatic heterocyclic group (e.g., benzothienyl), further preferably,

phenyl.

The “aromatic ring group” of the “optionally substituted aromatic ringgroup” for ring A group is optionally substituted by 1 to 5 (preferably1 to 3, more preferably 1 or 2) substituents other than —NH—CO—CH₂—group at substitutable position(s). Examples of such substituent includethe above-mentioned “substituent”, preferably, (1) a halogen atom (e.g.,fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) anoptionally substituted C₁₋₆ alkyl group (e.g., methyl), (4) anoptionally substituted C₆₋₁₄ aryl group (e.g., phenyl), (5) anoptionally substituted C₁₋₆ alkoxy group (e.g., methoxy), or (6) anoptionally substituted 5- to 14-membered aromatic heterocyclic group(e.g., thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,triazolyl, pyridyl, pyridazinyl), more preferably,

(1) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom),(2) a cyano group, (3) a C₁₋₆ alkyl group (e.g., methyl) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine atom), (4) a C₆₋₁₄aryl group (e.g., phenyl), (5) a C₁₋₆ alkoxy group (e.g., methoxy), or(6) a 5- to 14-membered aromatic heterocyclic group (e.g., thienyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl,pyridazinyl) optionally substituted by 1 to 3 substituents selected from(i) a cyano group, (ii) a halogen atom (e.g., chlorine atom), (iii) aC₁₋₁₂ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, isopentyl, dodecyl) optionally substituted by 1 to6 substituents selected from (a) a halogen atom (e.g., fluorine atom),(b) a cyano group, (c) a hydroxy group, (d) a C₃₋₁₀ cycloalkyl group(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine atom), (e) a C₁₋₆alkoxy group (e.g., methoxy, ethoxy) optionally substituted by a C₁₋₆alkoxy group (e.g., methoxy), (f) a C₆₋₁₄ aryl group (e.g., phenyl), (g)a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,tert-butoxycarbonyl), (h) a carbamoyl group, (i) a C₁₋₆ alkyl-sulfonylgroup (e.g., methylsulfonyl), (j) a 3- to 14-membered non-aromaticheterocyclic group (e.g., oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl) and (k) a 5- to 14-membered aromaticheterocyclic group (e.g., pyrazolyl, imidazolyl, pyridyl), (iv) a C₃₋₁₀cycloalkyl group (e.g., cyclopropyl, cyclopentyl), (v) a 3- to14-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl),(vi) a C₁₋₆ alkoxy-carbonyl (e.g., tert-butoxycarbonyl) and (vii) an oxogroup, further preferably,

(1) a halogen atom (e.g., fluorine atom) or (2) a 5- to 14-memberedaromatic heterocyclic group (e.g., pyrazolyl, triazolyl) optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl).

Ring A group is preferably

a C₆₋₁₄ aryl group (e.g., phenyl, naphthyl) or an aromatic heterocyclicgroup (thienyl, benzothienyl), each of which is optionally substitutedby 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituentsselected from (1) a halogen atom (e.g., fluorine atom, chlorine atom,bromine atom), (2) a cyano group, (3) an optionally substituted C₁₋₆alkyl group (e.g., methyl), (4) an optionally substituted C₆₋₁₄ arylgroup (e.g., phenyl), (5) an optionally substituted C₁₋₆ alkoxy group(e.g., methoxy) and (6) an optionally substituted 5- to 14-memberedaromatic heterocyclic group (e.g., thienyl, pyrazolyl, imidazolyl,thiazolyl, isothiazolyl, triazolyl, pyridyl, pyridazinyl), morepreferably,

a C₆₋₁₄ aryl group (e.g., phenyl, naphthyl), a 5- or 6-memberedmonocyclic aromatic heterocyclic group (e.g., thienyl) or a 8- to14-membered fused polycyclic (preferably bicyclic or tricyclic) aromaticheterocyclic group (e.g., benzothienyl), each of which is optionallysubstituted by 1 to 5 (preferably 1 to 3, more preferably 1 or 2)substituents selected from (1) a halogen atom (e.g., fluorine atom,chlorine atom, bromine atom), (2) a cyano group, (3) a C₁₋₆ alkyl group(e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine atom), (4) a C₆₋₁₄ aryl group (e.g., phenyl), (5) a C₁₋₆ alkoxygroup (e.g., methoxy), and (6) a 5- to 14-membered aromatic heterocyclicgroup (e.g., thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,triazolyl, pyridyl, pyridazinyl) optionally substituted by 1 to 3substituents selected from (i) a cyano group, (ii) a halogen atom (e.g.,chlorine atom), (iii) a C₁₋₁₂ alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, isopentyl, dodecyl) optionallysubstituted by 1 to 6 substituents selected from (a) a halogen atom(e.g., fluorine atom), (b) a cyano group, (c) a hydroxy group, (d) aC₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine atom), (e) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy)optionally substituted by a C₁₋₆ alkoxy group (e.g., methoxy), (f) aC₆₋₁₄ aryl group (e.g., phenyl), (g) a C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, tert-butoxycarbonyl), (h) a carbamoyl group, (i) a C₁₋₆alkyl-sulfonyl group (e.g., methylsulfonyl), (j) a 3- to 14-memberednon-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl) and (k) a 5- to 14-membered aromaticheterocyclic group (e.g., pyrazolyl, imidazolyl, pyridyl), (iv) a C₃₋₁₀cycloalkyl group (e.g., cyclopropyl, cyclopentyl), (v) a 3- to14-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl),(vi) a C₁₋₆ alkoxy-carbonyl (e.g., tert-butoxycarbonyl) and (vii) an oxogroup, further preferably,

phenyl optionally substituted by 1 to 5 (preferably 1 to 3, morepreferably 1 or 2) substituents selected from (1) a halogen atom (e.g.,fluorine atom) and (2) a 5- to 14-membered aromatic heterocyclic group(e.g., pyrazolyl, triazolyl) optionally substituted by 1 to 3 C₁₋₆ alkylgroups (e.g., methyl).

R¹ is a hydrogen atom, a halogen atom, a cyano group, an optionallysubstituted alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted amino group, or an optionallysubstituted hydroxy group.

R¹ is preferably (1) a hydrogen atom, (2) a halogen atom (e.g., fluorineatom, chlorine atom, bromine atom), (3) an optionally substituted alkylgroup (e.g., methyl, ethyl), (4) an optionally substituted alkynyl group(e.g., 1-propynyl), or (5) an optionally substituted hydroxy group, morepreferably, (1) a hydrogen atom, (2) a halogen atom (e.g., fluorineatom, chlorine atom, bromine atom), (3) an alkyl group (e.g., methyl,ethyl) optionally substituted by 1 to 3 substituents selected from ahalogen atom (e.g., fluorine atom), a cyano group, a hydroxy group and aC₁₋₆ alkoxy group (e.g., methoxy), (4) an alkynyl group (e.g.,1-propynyl) optionally substituted by a hydroxy group, or (5) a hydroxygroup optionally substituted by a C₁₋₆ alkyl group (e.g., methyl),further preferably an alkyl group (e.g., methyl).

X¹ is CR² or a nitrogen atom, X² is CR³ or a nitrogen atom, and R² andR³ are each independently a hydrogen atom, a halogen atom, or anoptionally substituted alkyl group.

X¹ is preferably CR^(2a) (R^(2a) is a hydrogen atom or a halogen atom(e.g., fluorine atom)) or a nitrogen atom, more preferably CH.

X² is preferably CR^(3a) (R^(3a) is a hydrogen atom or a halogen atom(e.g., fluorine atom)) or a nitrogen atom, more preferably CH.

X³ is CR⁴R⁵ or NR⁶, X⁴ is CR⁷R⁸, X⁵ is CR⁹R¹⁰ or an oxygen atom, R⁴ is ahydrogen atom, a cyano group, an optionally substituted hydrocarbongroup, or an optionally substituted heterocyclic group, R⁵ is a cyanogroup, an optionally substituted hydrocarbon group, or an optionallysubstituted heterocyclic group, R⁴ and R⁵ are optionally bonded to eachother to form, together with the adjacent carbon atom, an optionallyfurther substituted ring, and R⁶, R⁷, R⁸, R⁹, and R¹⁰ are eachindependently a hydrogen atom, an optionally substituted hydrocarbongroup, or an optionally substituted heterocyclic group.

The “hydrocarbon group” of the “optionally substituted hydrocarbongroup” for R⁴ or R⁵ is preferably a C₁₋₆ alkyl group (e.g., methyl), aC₂₋₆ alkenyl group (e.g., 2-propenyl) or a C₃₋₁₀ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl).

X³ is preferably CR^(4a)R^(5a) (R^(4a) and R^(5a) are each independentlya cyano group, an optionally substituted C₁₋₆ alkyl group (e.g.,methyl), an optionally substituted C₂₋₆ alkenyl group (e.g., 2-propenyl)or an optionally substituted C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl)), more preferably, CR^(4b)R^(5b) (R^(4b) andR^(5b) are each independently a cyano group, a C₁_6 alkyl group (e.g.,methyl), a C₂₋₆ alkenyl group (e.g., 2-propenyl) or a C₃₋₁₀ cycloalkylgroup (e.g., cyclopropyl, cyclobutyl, cyclopentyl)), further preferably,CR^(4c)R^(5c) (R^(4c) and R^(5c) are each independently a cyano group ora C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl)).

In one embodiment of the present invention, a compound wherein X³ isCR⁴R⁵ and at least one of R⁴ and R⁵ is a cyano group is preferable.

The “hydrocarbon group” of the “optionally substituted hydrocarbongroup” for R⁷ or R⁸ is preferably a C₁₋₆ alkyl group (e.g., methyl), andthe substituent thereof is preferably a cyano group, a hydroxy group ora C₁₋₆ alkoxy group (e.g., methoxy).

X⁴ is preferably CR^(7a)R^(8a) (R^(7a) and R^(8a) are each independentlya hydrogen atom or an optionally substituted C₁₋₆ alkyl group (e.g.,methyl)), more preferably, CR^(7b)R^(8b) (R^(7b) and R^(8b) are eachindependently (1) a hydrogen atom or (2) a C₁₋₆ alkyl group (e.g.,methyl) optionally substituted by 1 to 3 substituents selected from acyano group, a hydroxy group and a C₁₋₆ alkoxy group (e.g., methoxy)),further preferably, CH₂.

The “hydrocarbon group” of the “optionally substituted hydrocarbongroup” for R⁹ or R¹⁰ is preferably a C₁₋₆ alkyl group (e.g., methyl).

X⁵ is preferably CR^(9a)R^(10a) (R^(9a) and R^(10a) are eachindependently a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup (e.g., methyl)), more preferably CR^(9b)R^(10b) (R^(9b) andR^(10b) are each independently a hydrogen atom or a C₁₋₆ alkyl group(e.g., methyl)), further preferably CH₂.

Preferable examples of compound (I) include the following compounds.

[Compound A]

Compound (I) wherein ring A group is a C₆₋₁₄ aryl group (e.g., phenyl,naphthyl) or an aromatic heterocyclic group (thienyl, benzothienyl),each of which is optionally substituted by 1 to 5 (preferably 1 to 3,more preferably 1 or 2) substituents selected from (1) a halogen atom(e.g., fluorine atom, chlorine atom, bromine atom), (2) a cyano group,(3) an optionally substituted C₁₋₆ alkyl group (e.g., methyl), (4) anoptionally substituted C₆₋₁₄ aryl group (e.g., phenyl), (5) anoptionally substituted C₁₋₆ alkoxy group (e.g., methoxy) and (6) anoptionally substituted 5- to 14-membered aromatic heterocyclic group(e.g., thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,triazolyl, pyridyl, pyridazinyl);

R¹ is (1) a hydrogen atom, (2) a halogen atom (e.g., fluorine atom,chlorine atom, bromine atom), (3) an optionally substituted alkyl group(e.g., methyl, ethyl), (4) an optionally substituted alkynyl group(e.g., 1-propynyl), or (5) an optionally substituted hydroxy group;

X¹ is CR^(2a) (R^(2a) is a hydrogen atom or a halogen atom (e.g.,fluorine atom)) or a nitrogen atom;

X² is CR^(3a) (R^(3a) is a hydrogen atom or a halogen atom (e.g.,fluorine atom)) or a nitrogen atom;

X³ is CR^(4a)R^(5a) (R^(4a) and R^(5a) are each independently a cyanogroup, an optionally substituted C₁₋₆ alkyl group (e.g., methyl), anoptionally substituted C₂₋₆ alkenyl group (e.g., 2-propenyl) or anoptionally substituted C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl));

X⁴ is CR^(7a)R^(8a) (R^(7a) and R^(ea) are each independently a hydrogenatom or an optionally substituted C₁₋₆ alkyl group (e.g., methyl)); and

X⁵ is CR^(9a)R^(10a) (R^(9a) and R^(10a) are each independently ahydrogen atom or an optionally substituted C₁₋₆ alkyl group (e.g.,methyl)).

[Compound B]

Compound (I) wherein ring A group is a C₆₋₁₄ aryl group (e.g., phenyl,naphthyl), a 5- or 6-membered monocyclic aromatic heterocyclic group(e.g., thienyl) or a 8- to 14-membered fused polycyclic (preferablybicyclic or tricyclic) aromatic heterocyclic group (e.g., benzothienyl),each of which is optionally substituted by 1 to 5 (preferably 1 to 3,more preferably 1 or 2) substituents selected from (1) a halogen atom(e.g., fluorine atom, chlorine atom, bromine atom), (2) a cyano group,(3) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., fluorine atom), (4) a C₆₋₁₄ aryl group (e.g.,phenyl), (5) a C₁₋₆ alkoxy group (e.g., methoxy), and (6) a 5- to14-membered aromatic heterocyclic group (e.g., thienyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyridazinyl)optionally substituted by 1 to 3 substituents selected from (i) a cyanogroup, (ii) a halogen atom (e.g., chlorine atom), (iii) a C₁₋₁₂ alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, isopentyl, dodecyl) optionally substituted by 1 to 6substituents selected from (a) a halogen atom (e.g., fluorine atom), (b)a cyano group, (c) a hydroxy group, (d) a C₃₋₁₀ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) optionally substitutedby 1 to 3 halogen atoms (e.g., fluorine atom), (e) a C₁₋₆ alkoxy group(e.g., methoxy, ethoxy) optionally substituted by a C₁₋₆ alkoxy group(e.g., methoxy), (f) a C₆₋₁₄ aryl group (e.g., phenyl), (g) a C₁₋₆alkoxy-carbonyl group (e.g., methoxycarbonyl, tert-butoxycarbonyl), (h)a carbamoyl group, (i) a C₁₋₆ alkyl-sulfonyl group (e.g.,methylsulfonyl), (j) a 3- to 14-membered non-aromatic heterocyclic group(e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl)optionally substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl) and(k) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,imidazolyl, pyridyl), (iv) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl,cyclopentyl), (v) a 3- to 14-membered non-aromatic heterocyclic group(e.g., tetrahydrofuranyl), (vi) a C₁₋₆ alkoxy-carbonyl (e.g.,tert-butoxycarbonyl) and (vii) an oxo group;

R¹ is (1) a hydrogen atom, (2) a halogen atom (e.g., fluorine atom,chlorine atom, bromine atom), (3) an alkyl group (e.g., methyl, ethyl)optionally substituted by 1 to 3 substituents selected from a halogenatom (e.g., fluorine atom), a cyano group, a hydroxy group and a C₁₋₆alkoxy group (e.g., methoxy), (4) an alkynyl group (e.g., 1-propynyl)optionally substituted by a hydroxy group, or (5) a hydroxy groupoptionally substituted by a C₁₋₆ alkyl group (e.g., methyl);

X¹ is CR^(2a) (R^(2a) is a hydrogen atom or a halogen atom (e.g.,fluorine atom)) or a nitrogen atom;

X² is CR^(3a) (R^(3a) is a hydrogen atom or a halogen atom (e.g.,fluorine atom)) or a nitrogen atom;

X³ is CR^(4b)R^(5b) (R^(4b) and R^(5b) are each independently a cyanogroup, a C₁₋₆ alkyl group (e.g., methyl), a C₂₋₆ alkenyl group (e.g.,2-propenyl) or a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl));

X⁴ is CR^(7b)R^(8b) (R^(7b) and R^(8b) are each independently (1) ahydrogen atom or (2) a C₁₋₆ alkyl group (e.g., methyl) optionallysubstituted by 1 to 3 substituents selected from a cyano group, ahydroxy group and a C₁₋₆ alkoxy group (e.g., methoxy)); and

X⁵ is CR^(9b)R^(10b) (R^(9b) and R^(10b) are each independently ahydrogen atom or a C₁₋₆ alkyl group (e.g., methyl)).

[Compound C]

Compound (I) wherein ring A group is phenyl optionally substituted by 1to 5 (preferably 1 to 3, more preferably 1 or 2) substituents selectedfrom (1) a halogen atom (e.g., fluorine atom) and (2) a 5- to14-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl)optionally substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl);

R¹ is an alkyl group (e.g., methyl);

X¹ is CH;

X² is CH;

X³ is CR^(4c)R^(5c) (R^(4c) and R^(5C) are each independently a cyanogroup or a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl));

X⁴ is CH₂; and

X⁵ is CH₂.

Specific examples of compound (I) include the compounds of thebelow-mentioned Examples 1-132.

Among those,

-   N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide    or a salt thereof, or,-   N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide    or a salt thereof is recited as a preferable example.

As a salt of a compound represented by the formula (I), apharmacologically acceptable salt is preferable. Examples of such saltinclude salts with inorganic base, salts with organic base, salts withinorganic acid, salts with organic acid, and salts with basic or acidicamino acid.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt, and the like; aluminumsalt; ammonium salt, and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine,benzylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike.

Preferable examples of the salt with inorganic acid include salts withhydrogen chloride, hydrobromic acid, nitric acid, sulfuric acid, andphosphoric acid.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, and ornithine.

Preferable examples of the salt with acidic amino acid include saltswith aspartic acid, and glutamic acid.

The production method of the compound of the present invention isexplained in the following.

The starting materials and reagents used in each step in the followingproduction method, and the obtained compounds each may form a salt.Examples of the salt include those similar to the aforementioned saltsof the compound of the present invention and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or a desired other kind of salt by a method known per se.

The compound obtained in each step can also be used for the nextreaction as a reaction mixture thereof or after obtaining a crudeproduct thereof. Alternatively, the compound obtained in each step canbe isolated and/or purified from the reaction mixture by a separationmeans such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography and thelike according to a conventional method.

When the starting materials and reagent compounds of each step arecommercially available, the commercially available products can be usedas they are.

In the reaction of each step, while the reaction time may vary dependingon the reagents and solvents to be used, unless otherwise specified, itis generally 1 min-48 hr, preferably 10 min-8 hr.

In the reaction of each step, while the reaction temperature may varydepending on the reagents and solvents to be used, unless otherwisespecified, it is generally −78° C. to 300° C., preferably −78° C. to150° C.

In the reaction of each step, while the pressure may vary depending onthe reagents and solvents to be used, unless otherwise specified, it isgenerally 1 atm-20 atm, preferably 1 atm-3 atm.

In the reaction of each step, for example, microwave synthesizers suchas Initiator manufactured by Biotage and the like are sometimes used.While the reaction temperature may vary depending on the reagents andsolvents to be used, unless otherwise specified, it is generally roomtemperature-300° C., preferably 50° C.-250° C. While the reaction timemay vary depending on the reagents and solvents to be used, unlessotherwise specified, it is generally 1 min-48 hr, preferably 1 min-8 hr.

In the reaction of each step, unless otherwise specified, a reagent isused in 0.5 equivalent-20 equivalents, preferably 0.8 equivalent-5equivalents, relative to the substrate. When a reagent is used as acatalyst, the reagent is used in 0.001 equivalent-1 equivalent,preferably 0.01 equivalent-0.2 equivalent, relative to the substrate.When the reagent is also a reaction solvent, the reagent is used in asolvent amount.

In the reaction of each step, unless otherwise specified, it isperformed without solvent or by dissolving or suspending in a suitablesolvent. Specific examples of the solvent include those described inExamples and the following. alcohols: methanol, ethanol, tert-butylalcohol, 2-methoxyethanol and the like;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;saturated hydrocarbons: cyclohexane, hexane and the like; amides:N,N-dimethylformamide, N-methylpyrrolidone and the like;halogenated hydrocarbon s: dichloromethane, carbon tetrachloride and thelike;nitriles: acetonitrile and the like;sulfoxides: dimethyl sulfoxide and the like;aromatic organic bases: pyridine and the like;acid anhydrides: acetic anhydride and the like; organic acids: formicacid, acetic acid, trifluoroacetic acid and the like;inorganic acids: hydrochloric acid, sulfuric acid and the like; esters:ethyl acetate and the like;ketones: acetone, methyl ethyl ketone and the like; and water.

Two or more kinds of the above-mentioned solvents may be used by mixingat an appropriate ratio.

When a base is used in the reaction of each step, for example, basesshown below or those described in Examples are used.

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate and the like;organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;alkali metal hydrides: sodium hydride and the like;metal amides: sodium amide, lithium diisopropyl amide, lithiumhexamethyl disilazide and the like; and organic lithiums: n-butyllithiumand the like.

When an acid or acidic catalyst is used in the reaction of each step,for example, acids and acidic catalysts shown below or those describedin Examples are used.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; andLewis acids: boron trifluoride diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

Unless otherwise specified, the reaction of each step is performedaccording to a method known per se, for example, the methods describedin Jikken Kagaku Kouza 5th edition, vol. 13-vol. 19 (The ChemicalSociety of Japan ed.); Shinjikken Kagaku Kouza (Courses in ExperimentalChemistry), vol. 14-vol. 15 (The Chemical Society of Japan ed.); FineOrganic Chemistry rev. 2nd edition (L. F. Tietze, Th. Eicher, NANKODO);rev. Organic Name Reactions, Their Mechanism and Essence (Hideo Togo,Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & SonsInc); Modern Organic Synthesis in the Laboratory, A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier JapanKK); Strategic Applications of Named Reactions in Organic Synthesis(translation supervisor Kiyoshi Tomioka, KAGAKUDOJIN); ComprehensiveOrganic Transformations (VCH Publishers Inc.), 1989 and the like, or themethods described in the Examples.

In each step, protection or deprotection reaction of a functional groupis performed by the method known per se, for example, the methodsdescribed in “Protective Groups in Organic Synthesis, 4th Ed.” (TheodoraW. Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; “ProtectingGroups 3rd Ed.” (P. J. Kocienski) Thieme, 2004 and the like, or themethods described in the Examples.

Examples of the protecting group of the hydroxyl group of alcohol andthe like and a phenolic hydroxyl group include ether protecting groupssuch as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether,tetrahydropyranyl ether and the like; carboxylate ester protectinggroups such as acetate ester and the like; sulfonate ester protectinggroups such as methanesulfonate ester and the like; carbonate esterprotecting groups such as t-butylcarbonate and the like, and the like.

Examples of the protecting group of the carbonyl group of aldehydeinclude acetal protecting groups such as dimethyl acetal and the like;cyclic acetal protecting groups such as cyclic 1,3-dioxane and the like,and the like.

Examples of the protecting group of the carbonyl group of ketone includeketal protecting groups such as dimethyl ketal and the like; cyclicketal protecting groups such as cyclic 1,3-dioxane and the like; oximeprotecting groups such as O-methyloxime and the like; hydrazoneprotecting groups such as N,N-dimethylhydrazone and the like, and thelike.

Examples of the protecting group for carboxy group include ester-typeprotecting groups such as methyl ester and the like; and amide-typeprotecting groups such as N,N-dimethylamide and the like.

Examples of the thiol protecting group include ether protecting groupssuch as benzyl thioether and the like; ester protecting groups such asthioacetate ester, thiocarbonate, thiocarbamate and the like, and thelike.

Examples of the protecting group of an amino group and an aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate protecting groups such as benzyl carbamate and the like; amideprotecting groups such as acetamide and the like; alkylamine protectinggroups such as N-triphenylmethylamine and the like, sulfonamideprotecting groups such as methanesulfonamide and the like, and the like.

The protecting group can be removed by a method known per se, forexample, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyliodide, trimethylsilyl bromide), a reduction method and the like.

When a reduction reaction is performed in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When a carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like is used.

When an oxidation reaction is performed in each step, examples of anoxidant to be used include peracids such as m-chloroperbenzoic acid(mCPBA), hydrogen peroxide, t-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; high valent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chrome such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide pyridine complex; osmium tetraoxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When a radical cyclization reaction is performed in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4,4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. In addition, examples of the radical reaction agent to beused include tributylstannane, tristrimethylsilylsilane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

When the Wittig reaction is performed in each step, examples of theWittig reagent to be used include alkylidenephosphoranes and the like.Alkylidenephosphoranes can be prepared by a method known per se, forexample, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is performed in each step, examples ofthe reagent to be used include phosphonoacetic acid esters such asmethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and thelike; and bases such as alkali metal hydrides, organic lithiums and thelike.

When Friedel-Crafts reaction is carried out in each step, a combinationof a Lewis acid and an acid chloride or a combination of a Lewis acidand an alkylating agent (e.g., an alkyl halide, an alcohol, an olefinetc.) is used as a reagent. Alternatively, an organic acid or aninorganic acid can also be used instead of a Lewis acid, and an acidanhydride such as acetic anhydride and the like can also be used insteadof an acid chloride.

When an aromatic nucleophilic substitution reaction is performed in eachstep, a nucleophilic agent (e.g., amines, imidazole and the like) and abase (e.g., basic salts, organic bases and the like) are used as thereagent.

When a nucleophilic addition reaction with carbanion, a nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) or anucleophilic substitution reaction with carbanion is performed in eachstep, examples of the base to be used for developing carbanion includeorganic lithiums, metal alkoxides, inorganic bases, organic bases andthe like.

When the Grignard reaction is performed in each step, examples of theGrignard reagent include aryl magnesium halides such as phenyl magnesiumbromide and the like; and alkyl magnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared bya method known per se, for example, by reacting alkyl halide or arylhalide with metal magnesium in ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is performed in each step, anactive methylene compound held between two electron-withdrawing groups(e.g., malonic acid, diethyl malonate, malononitrile and the like) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asthe reagents.

When the Vilsmeier-Haack reaction is performed in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide and thelike) are used as the reagents.

When an azidation reaction of alcohols, alkyl halides or sulfonateesters is performed in each step, examples of the azidation agent to beused include diphenylphosphoryl azide (DPPA), trimethylsilyl azide,sodium azide and the like. For example, when alcohols are azidated, amethod using diphenylphosphoryl azide and1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), a method using trimethylsilylazide and the Lewis acid and the like can be employed.

When a reductive amination reaction is performed in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused besides para-formaldehyde include aldehydes such as acetaldehydeand the like, ketones such as cyclohexanone and the like. When thesubstrate is a carbonyl compound, examples of the amines to be usedinclude ammonia, primary amines such as methylamine and the like;secondary amines such as dimethylamine and the like, and the like.

When the Mitsunobu reaction is performed in each step, azodicarboxylateesters (e.g., diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) and the like) and triphenylphosphine are used asthe reagents.

When an esterification reaction, amidation reaction or ureation reactionis performed in each step, examples of the reagent to be used includehalogenated acyl forms such as acid chloride, acid bromide and the like;and activated carboxylic acids such as acid anhydride, active esterform, sulfuric acid ester form and the like. Examples of the carboxylicacid activator include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid;2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P);combinations thereof and the like. When carbodiimide condensing agent isused, an additive such as 1-hydroxybenzotriazole (HOBt),N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the likemay be further added to the reaction system.

When a coupling reaction is performed in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; nickel compounds such astetrakis(triphenylphosphine)nickel(0) and the like; rhodium compoundssuch as tris(triphenylphosphine)rhodium(III) chloride and the like; acobalt compound; copper compounds such as copper oxide, copper(I) iodideand the like; a platinum compound and the like. A base may be furtheradded to the reaction and examples of such base include inorganic bases,basic salts and the like.

When a thiocarbonylation reaction is performed in each step,diphosphorus pentasulfide is representatively used as athiocarbonylating agent. Besides diphosphorus pentasulfide, a reagenthaving a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) and the like may also be used.

When the Wohl-Ziegler reaction is performed in each step, examples ofthe halogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. Furthermore, the reaction can be accelerated byadding heat, light, radical initiators such as benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When a halogenating reaction of a hydroxy group is performed in eachstep, examples of the halogenating agent to be used include acid halideof hydrohalic acid and inorganic acid; specifically, hydrochloric acid,thionyl chloride, phosphorus oxychloride and the like for chlorination,and 48% is hydrobromic acid and the like for bromination. In addition, amethod of obtaining an alkyl halide form from alcohol by reacting withtriphenylphosphine and carbon tetrachloride or carbon tetrabromide, andthe like may be used. Alternatively, a method of synthesizing an alkylhalide form via a two-step reaction including conversion of alcohol tosulfonic acid ester, and reacting same with lithium bromide, lithiumchloride or sodium iodide may also be used.

When the Arbuzov reaction is performed in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

When a sulfonate esterification reaction is performed in each step,examples of the sulfonylating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride and the like.

When a hydrolysis reaction is performed in each step, an acid or a baseis used as the reagent. In addition, when an acid hydrolysis reaction oft-butyl ester is performed, formic acid, triethylsilane and the like aresometimes added to reductively trap the by-produced t-butyl cation.

When a dehydration reaction is performed in each step, sulfuric acid,phosphorus pentaoxide, phosphorus oxychloride,N,N′-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the likeare used as the dehydrating agent.

When an alkylation reaction of alcohols, amines, aromatic heterocycle(e.g., imidazole, pyrazole) having an NH group in the ring and the likeis performed in each step, optionally substituted alkyl halide (e.g.,iodomethane) or an optionally substituted alkyl having an optionallysubstituted C₁₋₆ alkylsulfonyloxy group as a leaving group, anoptionally substituted alkyl having a C₆₋₁₄ arylsulfonyloxy groupoptionally substituted by a C₁₋₆ alkyl group, or sodium2-chloro-2,2-difluoroacetate, 2,2-difluoro-2-(fluorosulfonyl)acetic acidand the like are used as the alkylating agents. In addition, organiclithiums, metal alkoxides, inorganic bases, organic bases and the likeare used as the base.

When a fluorination reaction is performed in each step, DAST(diethylaminosulfur trifluoride), bis(2-methoxyethyl)aminosulfurtrifluoride and the like are used as fluorinating agents.

When a coupling reaction is performed in each step, Suzuki coupling,Stille coupling, Buchwald coupling, Negishi coupling, Heck reaction,cyanation reaction using copper cyanide or zinc cyanide can be mentionedas the coupling reaction. Reagents used in a coupling reaction such asmetal catalyst, phosphine ligand, base and the like, in addition to theaforementioned reagents, can be used according to a method known per se[for example, methods described in J. F. Hartwig, S. Shekhar, Q. Shen,F. Barrios-Landeros, in The Chemistry of Anilines, Z. Rappoport, Ed.,Wiley-Intersicence, New York (2007); L. Jiang, S. L. Buchwald, inMetal-Catalyzed Cross-Coupling Reactions, 2^(nd) Ed., A. de Meijere, F.Diederich, Eds., Wiley-VCH, Weinheim, Germany (2004); J. F. Hartwig, inHandbook of Organopalladium Chemistry for Organic Synthesis, A. deMeijere, F. Diederich, Eds., Wiley, New York (2002); J. F. Hartwig, inModern Amination Methods, A. Ricci, Ed., Wiley-VCH, Weinheim, (2000)],or a method analogous thereto.

Examples of the leaving group to be used in each step include a halogenatom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), aC₁₋₆ alkoxy group (e.g., methoxy etc.), a C₆₋₁₄ aryloxy group (e.g.,phenoxy etc.), an optionally substituted acyl-oxy group (e.g.,acetyloxy, benzoyloxy etc.), an optionally substituted C₁₋₆alkoxysulfonyloxy group (e.g., methoxysulfonyloxy etc.), an optionallyhalogenated C₁₋₆ alkylsulfonyloxy group [e.g., methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy,trifluoromethanesulfonyloxy (triflate) etc.], an optionally substitutedC₆₋₁₄ arylsulfonyloxy group [e.g., C₆₋₁₄ arylsulfonyloxy groupoptionally having 1 to 3 substituents selected from C₁₋₆ alkyl group(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.), C₁₋₆ alkoxy group (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) and nitro group and the like; specific examples includebenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy,naphthylsulfonyloxy etc.] and the like.

The production method of compound (I) is described below.

Unless otherwise specified, each symbol in the following reactionformulas is as defined above. The starting compounds are easilycommercially available when a specific production method is notdescribed, or can be produced by a method known per se or a methodanalogous thereto.

[Production Method 1]

Compound (I) can be produced, for example, from compound (2) by themethod shown in the following Reaction Scheme 1 or a method analogousthereto.

wherein Y¹ and Y² are leaving groups.

compound (4), compound (5) and compound (6) may be commerciallyavailable or may also be produced by a method known per se (e.g., methoddescribed in patent document (WO 2015/016206) and the like) or a methodanalogous thereto.

The coupling reaction may also be performed in the presence of aphosphine ligand.

Examples of the above-mentioned phosphine ligand include1,1′-bis(diphenylphosphino)ferrocene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triphenylphosphine,tris(2-methylphenyl)phosphine, bis(diphenylphosphino)ferrocene,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphineand the like.

Compound (2) and compound (7) may be commercially available, or can alsobe produced by a method known per se (e.g., the methods described in theFifth Series of Experimental Chemistry, vol. 13-vol. 19 (The ChemicalSociety of Japan ed.); Experimental Chemistry, vol. 14-vol. 15 (TheChemical Society of Japan ed.); Fine Organic Chemistry, rev. 2nd edition(L. F. Tietze, Th. Eicher, NANKODO); rev. Organic Name Reaction (HideoTogo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley &SonsInc); Modern Organic Synthesis in the Laboratory A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (ElsevierJapan); Strategic Applications of Named Reactions in Organic Synthesis(Kiyoshi Tomioka, supervisor of translation, KAGAKUDOJIN); ComprehensiveOrganic Transformations (VCH Publishers Inc.) 1989 and the like), or amethod analogous thereto.

The substituent of the thus-obtained compound (I) is converted (that is,introduction of a substituent or conversion of a functional group) byapplying means known per se to produce another compound or a saltthereof encompassed in compound (I).

As a method for introduction of substituent or conversion of functionalgroup, a known general method is used. For example, conversion ofhalogen atom (e.g., fluorine, chlorine, bromine, iodine), optionallyhalogenated C₁₋₆ alkylsulfonyl-oxy group [e.g., methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy,trifluoromethanesulfonyloxy (triflate)] to methyl group, cyclopropylgroup, vinyl group, cyano group, formyl group, carbonyl group, carboxylgroup, hydroxyl group, amino group, boryl group and the like, conversionof formyl group to ethynyl group by Seyferth-Gilbert homologationreaction, conversion of ester to carboxy group by hydrolysis, conversionof carboxy group to carbamoyl group by amidation, conversion of carboxygroup to hydroxymethyl group by reduction, conversion of carbonyl groupto alcohol form by reduction or alkylation, reductive amination ofcarbonyl group, oximation of carbonyl group, acylation of amino group,ureation of amino group, sulfonylation of amino group, alkylation ofamino group, substitution or amination of active halogen by amine,alkylation of hydroxy group, substitution or amination of hydroxy groupcan be mentioned.

In the introduction of substituent and conversion of functional group,when a reactive site possibly causing a reaction other than the desiredreaction is present, a protecting group is introduced as necessary intothe reactive site in advance by means known per se, the object reactionis performed, and then the protecting group is also removed by meansknown per se, whereby a compound within the scope of the presentinvention can also be produced.

When the starting compound and intermediate have an amino group, acarboxy group or a hydroxy group as a substituent, these groups may beprotected by a protecting group generally used in the peptide chemistryand the like. In this case, the object compound can be obtained byeliminating the protecting group as necessary after the reaction.

Compound (I) obtained by the above-mentioned production method can beisolated and purified by a known means such as solvent extraction,conversion of solution pH, phase transfer, crystallization,recrystallization and chromatography.

When compound (I) has an optical isomer, a stereoisomer, a regioisomeror a rotamer, these are also encompassed in compound (I), and can beobtained as a single product according to synthesis and separationmethods known per se. For example, when compound (I) contains an opticalisomer, an optical isomer resolved from this compound is alsoencompassed in compound (I)

The optical isomer can be produced according to a method known per se.

Compound (I) may be a crystal.

A crystal of compound (I) (hereinafter sometimes to be abbreviated asthe crystal of the present invention) can be produced by crystallizingcompound (I) by applying a crystallization method known per se.

The crystal of the present invention is superior in physicochemicalproperties (e.g., melting point, solubility, stability) and biologicalproperties (e.g., pharmacokinetics (absorbability, distribution,metabolism, excretion), efficacy expression) and expected to be usefulas a medicament.

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization methods known per se.

Compound (I) may be a hydrate, non-hydrate, non-solvate or solvate.

Furthermore, compound (I) also encompasses a deuterium conversion formwherein 1H is converted to ²H(D).

Compound (I) may be labeled with an isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸F,³³S, ¹²⁵I) and the like. Compound (I) labeled or substituted with anisotope may be used as, for example, a tracer (PET tracer) used forPositron Emission Tomography (PET), and is expected to be useful in thefields of medical diagnosis and the like.

Compound (I) may be used as a prodrug.

The prodrug of compound (I) is a compound which is converted to compound(I) as a result of a reaction with an enzyme, gastric acid, etc. underphysiological conditions in vivo, thus a compound that undergoesenzymatic oxidation, reduction, hydrolysis etc. to convert to compound(I) and a compound that undergoes hydrolysis and the like by gastricacid, etc. to convert to compound (I).

Examples of the prodrug for compound (I) include a compound obtained bysubjecting an amino group in compound (I) to acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation);

a compound obtained by subjecting a hydroxy group in compound (I) toacylation, alkylation, phosphorylation or boration (e.g., a compoundobtained by subjecting a hydroxy group in compound (I) to acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation or dimethylaminomethylcarbonylation);a compound obtained by subjecting a carboxy group in compound (I) toesterification or amidation (e.g., a compound obtained by subjecting acarboxy group in compound (I) to ethyl esterification, phenylesterification, carboxymethyl esterification, dimethylaminomethylesterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethylesterification, phthalidyl esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification or methylamidation) and thelike. Any of these compounds can be produced from compound (I) accordingto a method known per se.

A prodrug of compound (I) may also be one which is converted to compound(I) under physiological conditions as described in “IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p.163-198 (HIROKAWA SHOTEN).

In the present specification, the prodrug may form a salt. Examples ofsuch salt include those exemplified as the salt of the aforementionedcompound represented by the formula (I).

Compound (I) or a prodrug thereof (hereinafter sometimes to be simplyabbreviated as the compound of the present invention) has a PRSinhibitory activity and may be useful as a prophylactic or therapeuticagent for cancer, a cancer proliferation inhibitor, or a cancermetastasis inhibitor.

The compound of the present invention shows a selective inhibitoryactivity against PRS. In addition, since the compound of the presentinvention is also superior in efficacy expression, pharmacokinetics(e.g., absorbability, distribution, metabolism, excretion), solubility(e.g., water-solubility), interaction with other pharmaceutical products(e.g., drug-metabolizing enzyme inhibitory action), safety (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,heart toxicity, carcinogenicity, central nervous system toxicity), andstability (e.g., chemical stability, stability against enzyme), it maybe useful as a medicament.

Therefore, the compound of the present invention may be used forinhibiting an excessive (abnormal) PRS action on mammals (e.g., mouse,rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human).

The compound of the present invention is expected to be useful for theprophylaxis or treatment of diseases possibly influenced by PRS(sometimes to be abbreviated as “PRS associated disease” in the presentspecification), for example, cancer [e.g., colorectal cancer (e.g.,colorectal cancer, rectal cancer, anal cancer, familial colorectalcancer, hereditary nonpolyposis colorectal cancer, gastrointestinalstromal tumor), lung cancer (e.g., non-small cell lung cancer, smallcell lung cancer, malignant mesothelioma), mesothelioma, pancreaticcancer (e.g., pancreatic duct cancer, pancreatic endocrine tumor),pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric cancer(e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamouscarcinoma), duodenal cancer, small intestinal cancer, breast cancer(e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatorybreast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma,extragonadal germ cell tumor, ovarian germ cell tumor, ovarian lowmalignant potential tumor), testis tumor, prostate cancer (e.g.,hormone-dependent prostate cancer, non-hormone dependent prostatecancer, castration-resistant prostate cancer), liver cancer (e.g.,hepatoma, primary liver cancer, extrahepatic bile duct cancer), thyroidcancer (e.g., medullary thyroid carcinoma), renal cancer (e.g., renalcell carcinoma (e.g., clear cell type renal cell carcinoma),transitional cell carcinoma in kidney and ureter), uterine cancer (e.g.,cervixcancer, uterine body cancer, uterus sarcoma), gestationalchoriocarcinoma, brain tumor (e.g., medulloblastoma, glioma, pinealastrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplasticastrocytoma, hypophyseal adenoma), retina blastoma, skin cancer (e.g.,basalioma, malignant melanoma (melanoma)), sarcoma (e.g.,rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cellsarcoma, osteosarcoma), malignant bone tumor, urinary bladder cancer,hematologic cancer (e.g., multiple myeloma, leukemia (e.g., acutemyeloid leukemia, acute lymphocytic leukemia), malignant lymphoma,Hodgkin's disease, chronic myeloproliferative disease), cancer ofunknown primary], inhibiting proliferation of cancer, suppression ofmetastasis, promotion of apoptosis, or prophylaxis or treatment ofprecancerous lesion (e.g., myelodysplastic syndrome). In addition, thecompound of the present invention is expected to be useful for theprophylaxis or treatment of scleroderma, cirrhosis, idiopathic pulmonaryfibrosis, inflammatory bowel disease or muscular dystrophy.

Also, the compound of the present invention is expected to be useful forthe prophylaxis or treatment of malaria.

The compound of the present invention may be administered orally orparenterally to a mammal (preferably, human) as it is or as a medicamentmixed with a pharmacologically acceptable carrier.

A medicament containing the compound of the present invention (sometimesto be abbreviated as “the medicament of the present invention”) isdescribed in detail below. Examples of the dosage form of the medicamentof the present invention include oral preparations such as tablet (e.g.,sugar-coated tablet, film-coated tablet, sublingual tablet, buccal,orally quick-integrating tablet), pill, granule, powder, capsule (e.g.,soft capsule, microcapsule), syrup, emulsion, suspension, film (e.g.,orally disintegrable film, mouth cavity mucosa patch film) and the like.Also, examples of the dosage form of the medicament of the presentinvention include parenteral agents such as injection, drip transfusion,transdermal agent (e.g., Iontophoresis transdermal preparation),suppository, ointment, nasal preparation, pulmonary preparation, eyedrop and the like. The medicament of the present invention may be acontrolled-release preparation such as immediate-release preparation,sustained-release preparation (e.g., sustained-release microcapsule) andthe like.

The medicament of the present invention may be produced by a knownproduction method (e.g., the method described in the JapanesePharmacopoeia) generally used in the technical field of preparationformulations. The medicament of the present invention can contain, wherenecessary, an appropriate amount of an additive generally used in thepharmaceutical field such as excipient, binder, disintegrant, lubricant,sweetening agent, surfactant, suspending agent, emulsifier, colorant,preservative, aromatic, corrigent, stabilizer, thickening agent and thelike.

These additives can be recited as the aforementioned pharmacologicallyacceptable carrier.

For example, tablet may be produced using excipient, binder,disintegrant, lubricant and the like, and pill and granule may beproduced using excipient, binder, disintegrant. In addition, powder andcapsule may be produced using excipient and the like, syrup may beproduced using sweetening agent and the like, and emulsion andsuspension may be produced using suspending agent, surfactant,emulsifier and the like.

Examples of the excipient include lactose, sucrose, glucose, starch,saccharose, microcrystalline cellulose, Glycyrrhiza uralensis, mannitol,sodium hydrogen carbonate, calcium phosphate, calcium sulfate.

Examples of the binder include 5 to 10 wt % starch glue solution, 10 to20 wt % gum arabic solution or gelatin solution, 1 to 5 wt % tragacanthsolution, carboxymethylcellulose solution, sodium alginate solution,glycerol.

Examples of the disintegrant include starch, calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate, purified talc.

Examples of the sweetening agent include glucose, fructose, invertsugar, sorbitol, xylitol, glycerol, simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester, polyoxyl stearate 40.

Examples of the suspending agent include gum arabic, sodium alginate,sodium carboxymethylcellulose, methylcellulose, bentonite.

Examples of the emulsifier include gum arabic, tragacanth, gelatin,polysorbate 80.

For example, when the medicament of the present invention is a tablet,the tablet may be produced according to a method known per se by adding,for example, excipient (e.g., lactose, sucrose, starch), disintegrant(e.g., starch, calcium carbonate), binder (e.g., starch, gum arabic,carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) orlubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000) tothe compound of the present invention, compression molding the mixtureand, where necessary, applying a coating for the purpose of tastemasking, enteric property or sustainability by a coating method knownper se. As the coating agent used for the coating,hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyoxyethyleneglycol, Tween 80, pluronic F68,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,hydroxymethylcellulose acetate succinate, Eudragit (manufactured byRohm, Germany, methacrylic acid-acrylic acid copolymer) and dye (e.g.,red iron oxide, titanium dioxide) may be used.

The aforementioned injection includes intravenous injection,subcutaneous injection, intradermal injection, muscular injection,intraperitoneal injection, drip injection and the like.

Such injection may be prepared by a method known per se, that is, bydissolving, suspending or emulsifying the compound of the presentinvention in an aseptic aqueous solution or oily solution. Examples ofthe aqueous solution include saline, isotonic solution (e.g.,D-sorbitol, D-mannitol, sodium chloride) containing glucose and otherauxiliary agents and the like. The aqueous solution may contain suitablesolubilizing agents, for example, alcohol (e.g., ethanol), polyalcohol(e.g., propylene glycol, polyethylene glycol), non-ionic surfactant(e.g., polysorbate 80, HCO-50). Examples of the oily solution includesesame oil, soybean oil and the like. The oily solution may contain asuitable solubilizing agent. Examples of the solubilizing agent includebenzyl benzoate, benzyl alcohol and the like. The injection may containbuffering agent (e.g., phosphate buffer, sodium acetate buffer),soothing agent (e.g., benzalkonium chloride, procaine hydrochloride),stabilizer (e.g., human serum albumin, polyethylene glycol),preservative (e.g., benzyl alcohol, phenol) and the like. An injectionthus prepared may be generally filled in an ampoule.

While the content of the compound of the present invention in themedicament of the present invention varies depending on the preparationform, it is generally about 0.01-about 100 wt %, preferably about2-about 85 wt %, further preferably about 5-about 70 wt %, relative tothe whole preparation.

While the content of the additive in the medicament of the presentinvention varies depending on the preparation form, it is generallyabout 1 to about 99.9 wt %, preferably about 10 to about 90 wt %,relative to the whole preparation.

The compound of the present invention is stable, low toxic and may beused safely. While the daily dose of the compound of the presentinvention varies depending on the condition and body weight of thepatients, kind of the compound, administration route and the like, when,for example, it is orally administered to patients for treating cancer,the dose for an adult (body weight about 60 kg) per day is about 1 toabout 1000 mg, preferably about 3 to about 300 mg, further preferablyabout 10 to about 200 mg, based on the compound of the presentinvention, which may be administered in one or two or three portions.

When the compound of the present invention is parenterally administered,it is generally administered in the form of a liquid (e.g., injection).While a single dose of the compound of the present invention variesdepending on the subject of administration, target organ, symptom,administration method and the like, for example, it is generallypreferable to administer about 0.01 to about 100 mg, preferably about0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, of thecompound of the present invention per 1 kg body weight by intravenousinjection.

The compound of the present invention may be used in combination withother drugs. Specifically, the compound of the present invention may beused in combination with drugs such as hormonal therapeutic agent,chemotherapeutic agent, immunotherapeutic agent or medicament inhibitingactions of cell growth factor and receptor thereof and the like. In thefollowing, a drug that can be used in combination with the compound ofthe present invention is to be abbreviated as a “concomitant drug”.

As the “hormonal therapeutic agent”, for example, fosfestrol,diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate,megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol,allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene,levormeloxifene, anti-estrogen (e.g., tamoxifen citrate, toremifenecitrate), pill preparation, mepitiostane, testrolactone,aminoglutethimide, LH-RH agonist (e.g., goserelin acetate, buserelin,leuprorelin acetate), droloxifene, epitiostanol, ethinylestradiolsulfonate, aromatase inhibitor (e.g., fadrozole hydrochloride,anastrozole, retrozole, exemestane, vorozole, formestane), anti-androgen(e.g., flutamide, bicartamide, nilutamide, enzalutamide), 5α-reductaseinhibitor (e.g., finasteride, epristeride, dutasteride), adrenocorticalhormone drug (e.g., dexamethasone, predonisolone, betamethasone,triamcinolone), androgen synthesis inhibitor (e.g., abiraterone),retinoid and drugs that retard retinoid metabolism (e.g., liarozole),thyroid gland hormone, and DDS (Drug Delivery System) preparationthereof are used.

As the “chemotherapeutic agent”, for example, alkylating agents,metabolic antagonists, antitumor antibiotics, and plant-derivedantitumor drugs may be used.

As the “alkylating agent”, for example, nitrogen mustard, nitrogenmustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide,ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan,nimustine hydrochloride, mitobronitol, melphalan, dacarbazine,ranimustine, estramustine phosphate sodium, triethylenemelamine,carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin,cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine,ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine,pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide,zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and DDSpreparations thereof may be used.

As the “metabolic antagonist”, for example, mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed,enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride,5-FU drug (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,gallocitabine, emitefur, capecitabine), aminopterin, nelzarabine,leucovorin calcium, tabloid, butocine, folinate calcium, levofolinatecalcium, cladribine, emitefur, fludarabine, gemcitabine,hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone,tiazofurin, ambamustine, bendamustine, and DDS preparations thereof maybe used.

As the “antitumor antibiotic”, for example, actinomycin D, actinomycinC, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycinsulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicinhydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride,epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin,carzinophilin, mitotane, zorubicin hydrochloride, mitoxantronehydrochloride, idarubicin hydrochloride, and DDS preparations thereof(e.g., Doxorubicin encapsulated PEG ribosome) may be used.

As the “plant-derived antitumor drug”, for example, etoposide, etoposidephosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate,teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDSpreparations thereof may be used.

As the “immunotherapeutic agent”, for example, picibanil, krestin,schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophagecolony stimulating factor, granulocyte colony stimulating factor,erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum,levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody (e.g.,ipilimumab, tremelimumab), anti-PD-1 antibody (e.g., nivolumab,pembrolizumab), anti-PD-L1 antibody may be used.

The “cell growth factors” in the “medicament inhibiting actions of cellgrowth factor and receptor thereof” may be any substance that promotescell proliferation, which is normally peptide having not more than20,000 molecular weight, and capable of exhibiting the activity at lowconcentrations by binding to a receptor, and specifically

(1) EGF (epidermal growth factor) or substances possessing substantiallythe same activity as EGF (e.g., TGFα);(2) insulin or substances possessing substantially the same activity asinsulin (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2),(3) FGF (fibroblast growth factor) or substances possessingsubstantially the same activity as FGF (e.g., acidic FGF, basic FGF, KGF(keratinocyte growth factor), FGF-10), and(4) other cell growth factors (e.g., CSF (colony stimulating factor),EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor),PDGF (platelet-derived growth factor), TGFβ (transforming growth factorβ), HGF (hepatocyte growth factor), VEGF (vascular endothelial growthfactor), heregulin, angiopoietin); may be used.

The “cell growth factor receptor” may be any receptor capable of bindingto the aforementioned cell growth factors, and specifically, EGFreceptor, heregulin receptor (e.g., HER3), insulin receptor, IGFreceptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGFreceptor, angiopoietin receptor (e.g., Tie2), PDGF receptor, and thelike may be used.

As the “medicament inhibiting actions of cell growth factor and receptorthereof”, for example, EGF inhibitor, TGFα inhibitor, heregulininhibitor, insulin inhibitor, IGF inhibitor, FGF inhibitor, KGFinhibitor, CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor,PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor,angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4inhibitor, insulin receptor inhibitor, IGF-1 receptor inhibitor, IGF-2receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor,FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptorinhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Rafinhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKCinhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor,Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK(MEK1/2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERKinhibitor, PI3K inhibitor, and the like may be used. More specifically,anti-VEGF antibody (e.g., Bevacizumab, Ramucurumab), anti-HER2 antibody(e.g., Trastuzumab, Pertuzumab), anti-EGFR antibody (e.g., Cetuximab,Panitumumab, Matuzumab, Nimotuzumab), anti-HGF antibody, Imatinib,Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib,Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib,Vismodegib, Axitinib, Motesanib, Nilotinib,6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin,Tozasertib,2-[N-[3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethylphosphate (AZD-1152),4-[9-chloro-7-(2,6-difluorophenyl)-5H-primido[5,4-d][2]benzazepin-2-ylamino]benzoicacid,N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycinesodium salt (ON-1910Na), Volasertib, Selumetinib, Trametinib,N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide(PD-0325901), Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib,Dabrafenib, and the like may be used.

Besides the above-mentioned drugs, asparaginase, aceglatone,procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercurichematoporphyrin-sodium, topoisomerase I inhibitor (e.g., irinotecan,topotecan, indotecan, Indimitecan), topoisomerase II inhibitor (e.g.,sobuzoxane), differentiation-inducing factor (e.g., retinoid, vitaminD), other angiogenesis inhibitor (e.g., fumagillin, shark extract, COX-2inhibitor), α-blocker (e.g., tamsulosin hydrochloride), bisphosphonicacid (e.g., pamidronate, zoledronate), thalidomide, lenalidomide,pomalidomide, 5-azacytidine, decitabine, proteasome inhibitor (e.g.,bortezomib, carfilzomib, ixazomib), NEDD8 inhibitor (e.g.,Pevonedistat), UAE inhibitor, PARP inhibitor (e.g., Olaparib, Niraparib,Veliparib), antitumor antibodies such as anti-CD20 antibody (e.g.,Rituximab, Obinutuzumab), anti-CCR4 antibody (e.g., Mogamulizumab) andthe like, antibody drug complex (e.g., trastuzumab emtansine,brentuximab vedotin), and the like may also be used as a concomitantdrug.

By combining the compound of the present invention and a concomitantdrug, superior effects such as (1) the dose can be reduced as comparedto single administration of the compound of the present invention or aconcomitant drug, (2) the drug to be combined with the compound of thepresent invention can be selected according to the condition of patients(mild case, severe case and the like), (3) the period of treatment canbe set longer, (4) a sustained treatment effect can be designed, (5) asynergistic effect can be afforded by a combined use of the compound ofthe present invention and a concomitant drug, and the like, can beachieved.

In the following, the compound of the present invention and aconcomitant drug used in combination are referred to as the “combinationagent of the present invention”.

When the combination agent of the present invention is administered, theadministration period is not limited and the compound of the presentinvention and the concomitant drug may be administered simultaneously,or may be administered at a time interval to an administration subject.When administered at a time interval, the interval varies depending onthe effective ingredient, dosage form and administration method, and,for example, when the concomitant drug is administered first, a methodin which the compound of the present invention is administered withintime range of from 1 minute to 3 days, preferably from 10 minutes to 1day, more preferably from 15 minutes to 1 hour, after administration ofthe concomitant drug is an example. When the compound of the presentinvention is administered first, a method in which the concomitant drugis administered within time range of from 1 minute to 1 day, preferablyfrom 10 minutes to 6 hours, more preferably from 15 minutes to 1 hourafter administration of the compound of the present invention is anexample. The dosage of the concomitant drug may be determined accordingto the dose clinically used, and can be appropriately selected dependingon an administration subject, administration route, disease, combinationand the like.

As the administration mode of the compound of the present invention andthe concomitant drug, the following methods can be mentioned: (1) Thecompound of the present invention and the concomitant drug aresimultaneously formulated to give a single preparation which isadministered. (2) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered simultaneously by the sameadministration route. (3) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered by the same administration route atstaggered times. (4) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered simultaneously by the differentadministration routes. (5) The compound of the present invention and theconcomitant drug are to separately formulated to give two kinds ofpreparations which are administered by the different administrationroutes at staggered times (e.g., the compound of the present inventionand the concomitant drug are administered in this order, or in thereverse order), and the like.

The dose of the concomitant drug may be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug may beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.For example, when the subject of administration is a human, 0.01 to 100parts by weight of a concomitant drug may be used per 1 part by weightof the compound of the present invention.

Furthermore, the compound of the present invention or the combinationagent of the present invention may be used in combination with anon-drug therapy. Specifically, the compound of the present invention orthe combination agent of the present invention may be combined with anon-drug therapy such as (1) surgery, (2) pressurized chemotherapy usingangiotensin II and the like, (3) gene therapy, (4) hyperthermic therapy,(5) cryotherapy, (6) laser cautery method, (7) radiation therapy.

For example, using the compound of the present invention or thecombination agent of the present invention before or after theaforementioned surgery or the like, or before or after a treatmentcombining two or three kinds of these, effects such as prevention ofresistance expression, elongation of disease-free period (Disease-FreeSurvival), suppression of cancer metastasis or recurrence,life-prolongation and the like may be achieved.

In addition, a treatment by the compound of the present invention or thecombination agent of the present invention and a supporting therapy [(i)administration of various antibiotics (e.g., β-lactams such as pansporinand the like, macrolides such as clarithromycin and the like) forcombination of infectious diseases, (ii) administration of intravenoushyperalimentation, amino acid preparation, general vitamin preparationfor improvement of malnutrition, (iii) administration of morphine forrelieving pain, (iv) administration of medicaments that improve sideeffects such as nausea, vomiting, anorexia, diarrhea, leucopenia,thrombocytopenia, hemoglobin concentration reduction, hair loss,hepatopathy, renopathy, DIC, fever and the like and (v) administrationof medicaments that suppress resistance of cancer to multiple drugs] mayalso be combined.

EXAMPLES

The present invention is further explained in detail by referring to thefollowing Examples, Experimental Examples and Formulation Examples whichdo not limit the present invention and may be changed without departingfrom the scope of the present invention.

The “room temperature” in the following Examples indicates the range ofgenerally from about 10° C. to about 35° C. The ratio for a mixedsolvent is, unless otherwise specified, a volume mixing ratio and %means wt % unless otherwise specified.

In silica gel column chromatography, the indication of NH means use ofaminopropylsilane-bonded silica gel, the indication of Diol means use of3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel, and theindication of DiNH means use ofN-(2-aminoethyl)-3-aminopropylsilane-bonded silica gel. In HPLC (highperformance liquid chromatography), the indication of C18 means use ofoctadecyl-bonded silica gel. The ratio of elution solvents is, unlessotherwise specified, a volume mixing ratio.

In Examples, the following abbreviations are used.

mp: melting pointMS: mass spectrum[M+H]⁺, [M−H]⁻: molecular ion peakM: mol concentrationN: N: normalCDCl₃: deuterochloroformDMSO-d₆: deuterodimethyl sulfoxide¹H NMR: proton nuclear magnetic resonanceLC/MS: liquid chromatograph mass spectrometerESI: electron spray ionizationAPCI: atmospheric pressure chemical ionizationIPE: isopropyl etherDME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide

Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)PdCl₂(dppf): [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichlorideTEA: triethylamineTHF: tetrahydrofuranTFA: trifluoroacetic acidT3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxideXantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

¹H NMR was measured by Fourier-transform NMR. For the analysis,ACD/SpecManager (trade name) and the like were used. Very mild peaks forprotons of a hydroxy group, an amino group and the like are notdescribed.

MS was measured by LC/MS. As the ionization method, ESI method, or APCImethod was used. The data indicates those found. Generally, molecularion peak ([M+H]⁺, [M−H]⁻ and the like) is observed; however, when thecompound has a tert-butoxycarbonyl group, a peak after elimination of atert-butoxycarbonyl group or tert-butyl group may be observed as afragment ion. When the compound has a hydroxyl group, a peak afterelimination of H₂O may be observed as a fragment ion. In the case of asalt, a molecular ion peak or fragment ion peak of free form isgenerally observed.

The unit of sample concentration (c) in optical rotation ([α]_(D)) isg/100 mL.

The elemental analytical value (Anal.) indicates Calculated value(Calcd) and measured value (Found).

Example 52N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamideA) 4-iodo-6-methylpyridin-2-amine

A mixture of 2-fluoro-4-iodo-6-methylpyridine (400 mg) and 28% aqueousammonia solution (2.8 mL) was stirred under microwave irradiation at135° C. for 6 hr. The reaction mixture was cooled to room temperature,and the precipitate was collected by filtration and washed with water togive the title compound (343.4 mg).

MS: M+1 235.0.

B)(3S)-1-(2-amino-6-methylpyridin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile

A mixture of 4-iodo-6-methylpyridin-2-amine (343.4 mg), copper(I) iodide(112 mg), N,N′-dimethylethylenediamine (63.1 μL), potassium carbonate(406 mg), (3S)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (242 mg)and DME (15 mL) was stirred under microwave irradiation at 130° C. for 1hr. The insoluble material was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (352.0 mg).

MS: M+1 257.3.

C) (3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetic acid

A mixture of 2-(3-bromo-5-fluorophenyl)acetic acid (400.4 mg),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(818.5 mg), PdCl₂(dppf) (69.5 mg), 2M aqueous potassium carbonatesolution (3.0 mL) and DME (10 mL) was stirred under a nitrogenatmosphere at 80° C. for 3 hr. To the reaction mixture was added waterat room temperature, and the aqueous layer was extracted with ethylacetate. To the aqueous layer was added 2N hydrochloric acid (6 mL) andthe mixture was further extracted with ethyl acetate. The combinedorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was collected by filtration and washed with IPE togive the title compound (287.1 mg).

MS: M+1 235.1.

D)N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide

A mixture of(3S)-1-(2-amino-6-methylpyridin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile(49.5 mg), 2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetic acid(63.8 mg), 1.7 M T3P/ethyl acetate solution (0.398 mL), TEA (0.135 mL)and ethyl acetate (2 mL) was stirred at 80° C. for 4 hr. To the reactionmixture was added water at room temperature, and the aqueous layer wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and then by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (83.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.40-0.72 (4H, m), 1.39-1.57 (1H, m),2.20-2.37 (1H, m), 2.42 (3H, s), 2.55-2.72 (1H, m), 3.74 (2H, s),3.83-3.96 (2H, m), 3.86 (3H, s), 6.91-7.02 (1H, m), 7.26-7.40 (3H, m),7.88 (1H, d, J=0.8 Hz), 8.18 (1H, s), 8.27 (1H, d, J=1.6 Hz), 10.75 (1H,s).

Example 57N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)acetamideA) methyl2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

A mixture of methyl 2-(3-bromo-5-fluorophenyl)acetate (1.78 g),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.98 g),PdCl₂(dppf) (0.257 g), potassium acetate (1.57 g) and DMF (20 mL) wasstirred under a nitrogen atmosphere at 80° C. for 16 hr. The insolublematerial was filtered off, water was added to the filtrate at roomtemperature, and the aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.55 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (12H, s), 3.62 (3H, s), 3.76 (2H, s),7.19-7.31 (2H, m), 7.41 (1H, s).

B) methyl 2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)acetate

A mixture of methyl2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(288 mg), 4-bromo-1-methyl-1H-1,2,3-triazole (132 mg), PdCl₂(dppf) (30.3mg), 2M aqueous potassium carbonate solution (1.0 mL) and toluene (4.0mL) was stirred under a nitrogen atmosphere at 100° C. for 2 hr. Theinsoluble material was filtered off, water was added to the filtrate atroom temperature, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(70.3 mg).

MS: M+1 250.1.

C) 2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)acetic acid

To a mixture of methyl2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)acetate (70.3 mg)and methanol (1 mL) was added 2N aqueous sodium hydroxide solution(0.423 mL) at room temperature. The reaction mixture was stirred at thesame temperature for 30 min. The reaction mixture was neutralized with2N hydrochloric acid and concentrated under reduced pressure. To theresidue were added ethyl acetate and THF, insoluble material wasfiltered off, and the filtrate was concentrated under reduced pressureto give the title compound (39.2 mg).

MS: M+1 236.1.

D)N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide

A mixture of(3S)-1-(2-amino-6-methylpyridin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile(37.4 mg), 2-(3-fluoro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)aceticacid (39.2 mg), 1.7 M T3P/ethyl acetate solution (0.300 mL), TEA (0.102mL) and ethyl acetate (2 mL) was stirred at 80° C. for 3 hr. To thereaction mixture was added water at room temperature, and the aqueouslayer was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (48.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.36-0.76 (4H, m), 1.36-1.59 (1H, m),2.22-2.37 (1H, m), 2.42 (3H, s), 2.55-2.72 (1H, m), 3.79 (2H, s),3.83-3.96 (2H, m), 4.09 (3H, s), 7.14 (1H, d, J=9.0 Hz), 7.33 (1H, d,J=1.7 Hz), 7.52 (1H, d, J=9.4 Hz), 7.71 (1H, s), 8.28 (1H, s), 8.57 (1H,s), 10.82 (1H, s).

Example 1262-(3-chlorophenyl)-N-(6-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-4-yl)acetamideA)(3S)-1-(6-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile

A mixture of 4,6-dichloropyrimidine (1.095 g),(3S)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (1.05 g), Pd₂(dba)₃(0.177 g), Xantphos (0.125 g), cesium carbonate (5.82 g) and THF (30 mL)was stirred under a nitrogen atmosphere at 70° C. for 2 hr. Theinsoluble material was filtered off, water was added to the filtrate atroom temperature, and the aqueous layer was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.42 g).

MS: M+1 263.0.

B)(3S)-1-(6-aminopyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile

A mixture of(3S)-1-(6-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile(972.1 mg), potassium carbonate (1.053 g),dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine-(2-(2-aminoethyl)phenyl)(chloro)palladium (1:1) (85.6 mg),dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(55.0 mg), 1-(2,4-dimethoxyphenyl)methanamine (0.612 mL) and tert-butylalcohol (20 mL) was stirred under an argon atmosphere at 100° C. for 2hr. The insoluble material was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give a solid(1130 mg). A mixture of the obtained solid (1130 mg) and TFA (3 mL) wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure, insoluble material was filteredoff, and the filtrate was diluted with ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution. The aqueous layer wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was washedwith an IPE/ethyl acetate mixed solvent to give the title compound (473mg). MS: M+1 244.1.

C)2-(3-chlorophenyl)-N-(6-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-4-yl)acetamide

A mixture of(3S)-1-(6-aminopyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile(68.9 mg), 2-(3-chlorophenyl)acetic acid (51.5 mg), 1.7 M T3P/ethylacetate solution (0.583 mL), TEA (0.197 mL) and ethyl acetate (2 mL) wasstirred at 80° C. for 1 hr. The reaction mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane), and the obtained solid was washedwith IPE to give the title compound (16 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.43-0.73 (4H, m), 1.41-1.58 (1H, m),2.25-2.41 (1H, m), 2.56-2.68 (1H, m), 3.80 (2H, s), 3.92-4.16 (2H, m),7.24-7.48 (4H, m), 8.74 (1H, d, J=1.1 Hz), 8.96 (1H, d, J=1.1 Hz), 11.17(1H, s).

Example 1292-(3-chlorophenyl)-N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)acetamideA)(3S)-1-(2-aminopyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile

A mixture of(3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile(602.8 mg), 1-(2,4-dimethoxyphenyl)methanamine (441 mg), TEA (0.385 mL)and 2-propanol (2 mL) was stirred under microwave irradiation at 150° C.for 40 min. The reaction mixture was concentrated under reducedpressure, and the residue was diluted with ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution, and the aqueous layer wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give an oil (734mg). A mixture of the obtained oil (734 mg) and TFA (5 mL) was stirredat room temperature for 30 min. The reaction mixture was concentratedunder reduced pressure, and the residue was diluted with ethyl acetateand saturated aqueous sodium hydrogen carbonate solution. The insolublematerial was filtered off, and the aqueous layer was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was washed with an ethyl acetate/hexanemixed solvent to give the title compound (368 mg).

MS: M+1 244.1.

B)2-(3-chlorophenyl)-N-(4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)acetamide

A mixture of(3S)-1-(2-aminopyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile(70.1 mg), 2-(3-chlorophenyl)acetic acid (63.9 mg), 1.7 M T3P/ethylacetate solution (0.509 mL), TEA (0.201 mL) and ethyl acetate (2 mL) wasstirred at 75° C. for 5 hr. To the reaction mixture was added a 1.7 MT3P/ethyl acetate solution (0.170 mL) at the same temperature, and thereaction mixture was stirred for 5 hr. The reaction mixture was dilutedwith ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (84 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.48-0.72 (4H, m), 1.47-1.57 (1H, m),2.26-2.41 (1H, m), 2.56-2.69 (1H, m), 3.88 (2H, s), 3.91-4.14 (2H, m),7.23-7.42 (4H, m), 7.88 (1H, d, J=5.7 Hz), 8.60 (1H, d, J=5.7 Hz), 10.83(1H, s).

According to the methods shown in the above-mentioned Examples or amethod analogous thereto, the compounds of Examples 1-51, 53-56, 58-125,127, 128, 130-132 in the following Tables were produced. Examplecompounds are shown in the following Tables. In the Tables, MS showsmeasured values.

TABLE 1-1 Ex. No. IUPAC name structural formula salt MS 12-(3-chlorophenyl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

395.1 2 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2- phenylacetamide

361.2 3 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(1- naphthyl)acetamide

411.2 4 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(2- naphthyl)acetamide

411.2 5 2-(2-chlorophenyl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

395.1 6 2-(4-chlorophenyl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

395.1

TABLE 1-2 Ex. No. IUPAC name structural formula salt MS  72-(biphenyl-2-yl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2- yl)acetamide

437.2  8 2-(biphenyl-4-yl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

437.2  9 2-(biphenyl-3-yl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

437.2 10 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- methoxyphenyl)acetamide

391.1 11 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- methylphenyl)acetamide

375.2 12 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(2,3- dichlorophenyl)acetamide

429.1

TABLE 1-3 Ex. No. IUPAC name structural formula salt MS 13N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- fluorophenyl)acetamide

379.2 14 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(2- fluorophenyl)acetamide

379.2 15 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- thienyl)acetamide

367.1 16 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(2- thienyl)acetamide

367.1 17 2-(5-chloro-2-thienyl)- N-(4-((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

401.0 18 N-(4-((3S,5R)-3-cyano-3- cyclopropyl-5-methyl-2-oxopyrrolidin-1- yl)pyridin-2-yl)-2- phenylacetamide

375.1

TABLE 1-4 Ex. No. IUPAC name structural formula salt MS 19N-(4-((3S,5S)-3-cyano-3- cyclopropyl-5-methyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2- phenylacetamide

375.1 20 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- phenylacetamide

375.1 21 2-(3-bromophenyl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

439.1 22 N-(4-((3R)-3-allyl-3- cyano-2-oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-methyl-1H-pyrazol-4- yl)phenyl)acetamide

441.1 23 N-(4-((3R)-3-allyl-3- cyano-2-oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (pyridin-3- yl)phenyl)acetamide

438.1 24 N-(4-((3R)-3-allyl-3- cyano-2-oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (3- thienyl)phenyl)acetamide

443.2

TABLE 1-5 Ex. No. IUPAC name structural formula salt MS 25N-(4-((3R)-3-allyl-3- cyano-2-oxopyrrolidin-1- yl)pyridin-2-yl)-2-(3-(pyridin-4- yl)phenyl)acetamide

438.1 26 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-methyl-1H-pyrazol-4- yl)phenyl)acetamide

441.1 27 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (1-naphthyl)acetamide

425.1 28 2-(1-benzothiophen-3- yl)-N-(4-((3S)-3-cyano- 3-cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

417.0 29 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (pyridin-4- yl)phenyl)acetamide

438.1 30 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide

455.2

TABLE 1-6 Ex. No. IUPAC name structural formula salt MS 31N-(4-(3-cyano-3- cyclopropyl-4- (hydroxymethyl)-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2- phenylacetamide

391.2 32 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(4- fluorophenyl)acetamide

379.2 33 N-(4-(3-cyano-3- cyclobutyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(1- naphthyl)acetamide

425.2 34 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (pyridin-3- yl)phenyl)acetamide

438.2 35 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- fluoro-5-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

459.2 36 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (5-cyano-2- thienyl)phenyl)acetamide

468.1

TABLE 1-7 Ex. No. IUPAC name structural formula salt MS 37N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-ethyl-1H-pyrazol-4- yl)phenyl)acetamide

455.2 38 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(2,2-difluoroethyl)- 1H-pyrazol-4-yl)phenyl)acetamide

491.2 39 N-(4-(3-cyano-4- (cyanomethyl)-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyridin-2-yl)-2- phenylacetamide

400.1 40 N-(4-(3-cyano-3- cyclopropyl-4- (methoxymethyl)-2-oxopyrrolidin-1- yl)pyridin-2-yl)-2- phenylacetamide

405.1 41 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-methyl-6-oxo-1,6- dihydropyridin-3-yl)phenyl)acetamide

468.2 42 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-cyclopropyl-1H- pyrazol-4- yl)phenyl)acetamide

467.2

TABLE 1-8 Ex. No. IUPAC name structural formula salt MS 43N-(4-(3,3-dimethyl-2- oxopyrrolidin-1- yl)pyridin-2-yl)-2-(3-(1-methyl-1H-pyrazol-4- yl)phenyl)acetamide

404.2 44 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(difluoromethyl)-1H- pyrazol-4-yl)phenyl)acetamide

477.2 45 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (2-methyl-1,3-thiazol-5- yl)phenyl)acetamide

458.1 46 N-(4-(3-cyano-3- cyclopentyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(1- naphthyl)acetamide

439.2 47 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-methyl-1H-1,2,3- triazol-4-yl)phenyl)acetamide

442.1 48 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (3-methyl-1,2-thiazol-5- yl)phenyl)acetamide

458.1

TABLE 1-9 Ex. No. IUPAC name structural formula salt MS 49N-(4-(3,3-dimethyl-2- oxopyrrolidin-1-yl)-6- methylpyridin-2-yl)-2-(3-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide

418.2 50 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1,2-thiazol-4- yl)phenyl)acetamide

444.2 51 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-methyl-2-oxo-1,2- dihydropyridin-4-yl)phenyl)acetamide

468.2 52 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-fluoro-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)acetamide

473.2 53 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(2- fluoro-5-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

459.2 54 N-(4-(3-cyano-3- cyclopropyl-4-methyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- phenylacetamide

387.0

TABLE 1-10 Ex. No. IUPAC name structural formula salt MS 55 tert-butyl4-(3-(2-((4- ((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)amino)-2- oxoethyl)phenyl)-1H- pyrazole-1-carboxylate

525.3 56 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1H- pyrazol-4- yl)phenyl)acetamide

427.2 57 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3- fluoro-5-(1-methyl-1H- 1,2,3-triazol-4-yl)phenyl)acetamide

474.2 58 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (2,2,2-trifluoroethyl)-1H- pyrazol-4-yl)phenyl)acetamide

509.2 59 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3- (1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)- phenyl)acetamide

523.2 60 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2-(3- fluoro-5-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)phenyl)acetamide

500.2

TABLE 1-11 Ex. No. IUPAC name structural formula salt MS 61N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-(trifluoromethyl)- pyridin-2-yl)-2-(3-(1- methyl-1H-pyrazol-4-yl)phenyl)acetamide

509.3 62 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methoxypyridin-2-yl)-2- (3-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide

471.1 63 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-fluoropyridin-2-yl)-2- (3-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide

459.1 64 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)phenyl)acetamide

481.3 65 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-(difluoromethyl)pyridin- 2-yl)-2-(3-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

491.2 66 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-cyclopentyl-1H- pyrazol-4- yl)phenyl)acetamide

495.3

TABLE 1-12 Ex. No. IUPAC name structural formula salt MS 67N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(2-hydroxyethyl)-1H- pyrazol-4-yl)phenyl)acetamide

471.2 68 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-isobutyl-1H-pyrazol- 4-yl)phenyl)acetamide

483.2 69 2-(3-(1-(2-amino-2- oxoethyl)-1H-pyrazol-4-yl)phenyl)-N-(4-((3S)-3- cyano-3-cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2- yl)acetamide

484.2 70 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(2-methoxyethyl)-1H- pyrazol-4-yl)phenyl)acetamide

485.2 71 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(3-cyanopropyl)-1H- pyrazol-4-yl)phenyl)acetamide

494.2 72 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(cyclobutylmethyl)- 1H-pyrazol-4-yl)phenyl)acetamide

495.3

TABLE 1-13 Ex. No. IUPAC name structural formula salt MS 73 methyl(4-(3-(2-((4- ((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)amino)-2- oxoethyl)phenyl)-1H- pyrazol-1-yl)acetate

499.1 74 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (3-methoxypropyl)-1H- pyrazol-4-yl)phenyl)acetamide

499.2 75 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (cyclopentylmethyl)-1H- pyrazol-4-yl)phenyl)acetamide

509.3 76 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (tetrahydrofuran-2- ylmethyl)-1H-pyrazol-4-yl)phenyl)acetamide

511.2 77 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- ((3-methyloxetan-3- yl)methyl)-1H-pyrazol-4-yl)phenyl)acetamide

511.2 78 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- ((2,2- difluorocyclopropyl)-methyl)-1H-pyrazol-4- yl)phenyl)acetamide

517.2

TABLE 1-14 Ex. No. IUPAC name structural formula salt MS 792-(3-(1-benzyl-1H- pyrazol-4-yl)phenyl)-N- (4-((3S)-3-cyano-3-cyclopropyl-2- oxopyrrolidin-1- yl)pyridin-2- yl)acetamide

517.2 80 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(2-(1H-pyrazol-1- yl)ethyl)-1H-pyrazol-4-yl)phenyl)acetamide

521.2 81 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(2-(1H-imidazol-1- yl)ethyl)-1H-pyrazol-4-yl)phenyl)acetamide

521.2 82 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(cyclohexylmethyl)- 1H-pyrazol-4-yl)phenyl)acetamide

523.3 83 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(tetrahydro-2H-pyran- 2-ylmethyl)-1H-pyrazol-4-yl)phenyl)acetamide

525.3 84 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(tetrahydro-2H-pyran- 4-ylmethyl)-1H-pyrazol-4-yl)phenyl)acetamide

525.3

TABLE 1-15 Ex. No. IUPAC name structural formula salt MS 85N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (1,4-dioxan-2-ylmethyl)- 1H-pyrazol-4-yl)phenyl)acetamide

527.2 86 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (2-(2- methoxyethoxy)ethyl)-1H- pyrazol-4-yl)phenyl)acetamide

529.2 87 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- ((3,3- difluorocyclobutyl)-methyl)-1H-pyrazol-4- yl)phenyl)acetamide

531.2 88 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (2-phenylethyl)-1H- pyrazol-4-yl)phenyl)acetamide

531.3 89 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (2- (methylsulfonyl)ethyl)- 1H-pyrazol-4-yl)phenyl)acetamide

533.3 90 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (4,4,4-trifluorobutyl)- 1H-pyrazol-4-yl)phenyl)acetamide

537.2

TABLE 1-16 Ex. No. IUPAC name structural formula salt MS 91N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- dodecyl-1H-pyrazol-4- yl)phenyl)acetamide

595.3 92 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (3,3,3-trifluoro-2- (trifluoromethyl)propyl)-1H-pyrazol-4- yl)phenyl)acetamide

591.2 93 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- isopropyl-1H-pyrazol-4- yl)phenyl)acetamide

469.2 94 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)phenyl)acetamide

497.2 95 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (2,2,3,3- tetrafluoropropyl)-1H- pyrazol-4-yl)phenyl)acetamide

541.3 96 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3-(1- (2,2,3,3,3- pentafluoropropyl)-1H- pyrazol-4-yl)phenyl)acetamide

559.2

TABLE 1-17 Ex. No. IUPAC name structural formula salt MS  97N-(6-bromo-4-((3S)-3- cyano-3-cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- fluoro-5-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

537.1  98 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-(1,5-dimethyl-1H- pyrazol-4-yl)phenyl)acetamide

469.2  99 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-ethylpyridin-2-yl)-2-(3- fluoro-5-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

487.2 100 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(3-hydroxy-3- methylbutyl)-1H-pyrazol-4-yl)phenyl)acetamide

513.2 101 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (1-(2-hydroxy-2- methylpropyl)-1H- pyrazol-4-yl)phenyl)acetamide

499.2 102 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-(1,3-dimethyl-1H- pyrazol-4-yl)phenyl)acetamide

469.3

TABLE 1-18 Ex. No. IUPAC name structural formula salt MS 103N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-(6-methylpyridazin-4- yl)phenyl)acetamide

467.2 104 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- (4H-1,2,4-triazol-4- yl)phenyl)acetamide

428.2 105 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-cyano-5-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

480.2 106 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-methyl-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)acetamide

469.3 107 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)acetamide

485.3 108 2-(3-chloro-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2- yl)acetamide

489.1

TABLE 1-19 Ex. No. IUPAC name structural formula salt MS 109N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-(3-hydroxyprop-1-yn-1- yl)pyridin-2-yl)-2-(3- fluoro-5-(1-methyl-1H-pyrazol-4- yl)phenyl)acetamide

513.2 110 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-3-fluoropyridin-2-yl)-2- (3-fluoro-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)acetamide

477.2 111 2-(3-bromo-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2- yl)acetamide

533.2 112 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-fluoro-5-(4-methyl- 1H-pyrazol-1-yl)phenyl)acetamide

473.2 113 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-fluoro-5-(1-(1- hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4- yl)phenyl)acetamide

531.3 114 N-(6-chloro-4-((3S)-3- cyano-3-cyclopropyl-2- oxopyrrolidin-1-yl)pyridin-2-yl)-2-(3- fluoro-5-(1-methyl-1H- pyrazol-4-yl)phenyl)acetamide

493.2

TABLE 1-20 Ex. No. IUPAC name structural formula salt MS 115N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-fluoro-5-(1H-pyrazol- 1-yl)phenyl)acetamide

459.2 116 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (4-(1-methyl-1H-pyrazol- 4-yl)-2-thienyl)acetamide

461.2 117 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-fluoro-5-(3- (hydroxymethyl)-1-methyl-1H-pyrazol-4- yl)phenyl)acetamide

503.2 118 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-(3,5-dimethyl-1H- pyrazol-1-yl)-5-fluorophenyl)acetamide

487.2 119 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-(methoxymethyl)pyridin- 2-yl)-2-(3-fluoro-5-(1- methyl-1H-pyrazol-4-yl)phenyl)acetamide

501.2 120 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-(hydroxymethyl)pyridin- 2-yl)-2-(3-fluoro-5-(1- methyl-1H-pyrazol-4-yl)phenyl)acetamide

487.2

TABLE 1-21 Ex. No. IUPAC name structural formula salt MS 121N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-fluoro-5-(1H- imidazol-1- yl)phenyl)acetamide

459.3 122 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-5-fluoropyridin-2-yl)-2- (3-fluoro-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)acetamide

477.2 123 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyridin-2-yl)-2- (3-(3,4-dimethyl-1H- pyrazol-1-yl)-5-fluorophenyl)acetamide

487.2 124 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-(cyanomethyl)pyridin-2- yl)-2-(3-fluoro-5-(1- methyl-1H-pyrazol-4-yl)phenyl)acetamide

498.3 125 N-(6-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyrimidin-4-yl)-2-(1- naphthyl)acetamide

412.2 126 2-(3-chlorophenyl)-N-(6- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyrimidin-4- yl)acetamide

396.2

TABLE 1-22 Ex. No. IUPAC name structural formula salt MS 127N-(6-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyrimidin-4-yl)-2- phenylacetamide

362.1 128 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)pyrimidin-2-yl)-2-(1- naphthyl)acetamide

412.2 129 2-(3-chlorophenyl)-N-(4- ((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyrimidin-2- yl)acetamide

396.2 130 2-(5-chloro-2-thienyl)- N-(4-((3S)-3-cyano-3- cyclopropyl-2-oxopyrrolidin-1- yl)pyrimidin-2- yl)acetamide

401.9 131 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyrimidin-2-yl)-2- phenylacetamide

376.1 132 N-(4-((3S)-3-cyano-3- cyclopropyl-2- oxopyrrolidin-1-yl)-6-methylpyrimidin-2-yl)-2- (3-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide

456.1

Experimental Example 1

The PRS inhibitory activity of the compounds of the present inventionwas evaluated by the following method.

An expression plasmid of Catalytic Domain of human EPRS was obtained byPCR using human skeletal muscle cDNA Library (Takara Bio Inc.) as atemplate and 2 kinds of Primers5′-ATAATAGCTAGCGAGAACCTGTACTTTCAGGGATCCTCAAGTGGAGCAGGAGAAGGGCA-3′(hEPRS-TEV-NheF) (SEQ ID NO: 1) and5′-ATAATAGCGGCCGCTCAGTAGCTGCGACCAAATAAGGT-3′ (hEPRS-St-Not-R) (SEQ IDNO: 2). PCR was performed using PrimeStar GXL DNA Polymerase (Takara BioInc.) and included (1) 98° C., 1 min, (2) cycles of 98° C., 10 sec, 65°C., 10 sec, 72° C., 1 min, and (3) reaction at 72° C., 1 min. This wascleaved with Nhe I and Not I (Takara Bio Inc.) and inserted usingLigation High (TOYOBO CO., LTD.) into the Nhe I/Not I site of pET21a(Novagen) with His-Avitag inserted thereinto. This was introduced intoECOS JM109 (NIPPON GENE CO., LTD.) to construct His-Avi-hEPRS (998-1512)expression plasmid.

Recombinant human PRS protein was prepared by transforming theHis-Avi-hEPRS (998-1512) expression plasmid prepared above into ECOSCompetent E. coli BL21(DE3) (NIPPON GENE CO., LTD.). Escherichia coliobtained by transformation was inoculated into 300 mL of LB medium (1%peptone, 0.5% yeast extract, 0.5% sodium chloride, 0.01% ampicillin) andcultured at 30° C. for 16 hr. The obtained culture medium wastransferred into a jar culture tank charged with 6 L of the mainfermentation medium (0.3% potassium dihydrogen phosphate, 0.6% disodiumhydrogen phosphate, 0.1% ammonium chloride, 0.05% sodium chloride,0.024% magnesium sulfate, 0.02% NEWPOL LB-625, 1.5% sorbitol, 1.5%casamino acid, 0.5% yeast extract, 0.01% ampicillin) and culturing wasstarted at 37° C., quantity of airflow 5 L/min, stirring rotating speed400 rpm. At the time point when the turbidity of the culture mediumreached about 550 Klett units, the culture temperature was lowered to16° C., isopropyl-β-D-thiogalactopyranoside (IPTG) was added to thefinal concentration 0.1 mM, and culturing was performed for another 16hr to induce expression of human PRS. After completion of culturing, theculture medium was centrifuged at 5,000 rpm for 10 min. The obtainedhuman PRS expressing Escherichia coli was suspended in a buffercontaining 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM DTT, 5 U/mlBenzonase, 20 mM Imidazole and sonicated using Sonifier (BRANSON). Thehomogenate was centrifuged (33,000×G, 60 min, Beckman Coulter), theobtained supernatant was subjected to adsorption by passage throughNi-NTA Superflow (QIAGEN) column equilibrated in advance with 50 mMTris-HCl (pH 8.0), 300 mM NaCl, 1 mM DTT, and elution was performed witha buffer containing 50 mM Tris-HCl (pH 8.0), 300 mM NaCl, 1 mM DTT, 250mM Imidazole. Furthermore, gel filtration was performed usingSuperdex200 μg column equilibrated in advance with a buffer containing50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM DTT, 10% glycerol to givepurified human PRS protein. The protein concentration was measured usingBCA Protein Assay Kit (PIERCE) and BSA as the standard.

A test compound was dissolved in 5 μL of an assay buffer (50 mM Tris-HCl(pH 7.5), 20 mM KCl, 1 mM DTT, 0.01% Tween 20) and incubated for 60 minwith 5 μL of 40 nM human PRS protein dissolved in the assay buffercontaining 40 mM MgCl₂. An enzyme reaction of the human PRS protein wasstarted by adding 10 μL of a substrate solution containing 300 μM ATP,160 μM L-Proline, 400 μM pyrophosphate, [³²P]pyrophosphate (PerkinElmer,Waltham, Mass.) prepared to 1 MBq/mL. After incubation at roomtemperature for 30 min, the reaction was discontinued by adding 50 μL ofdiscontinuation/washing solution (1M HCl, 200 mM sodium pyrophosphate)to the reaction mixture. The reaction solution was transferred to afilter plate (Merck Millipore, Billerica, Mass.) previously added with200 μL of charcoal solution (0.5% HCl solution containing 10% charcoal(w/v)). The filter plate was washed 5 times with washing solution, thelabeled resultant product was extracted into 96 well OptiPlate(PerkinElmer, Waltham, Mass.) with an extraction liquid (60% ethanol(v/v) containing 2M ammonia) and microscinti 20 (PerkinElmer, Waltham,Mass.) was added. The radioactivity was measured using TopCount(PerkinElmer, Waltham, Mass.). The inhibitory rate (%) of the testcompound was calculated with the radioactivity of a sample free of anenzyme reaction as 100% inhibition.

The inhibitory rate (%) of PRS with 300 nM test compound is shown inTable 2.

TABLE 2 Example No. inhibitory rate (%)  1 84  2 85  3 93  5 62  9 94 1088 11 85 13 89 14 70 15 84 16 88 17 83 20 94 21 89 22 87 24 71 25 61 26100  27 97 28 94 29 97 30 99 33 80 34 97 35 102  36 96 37 99 38 100  41101  42 100  43 88 44 100  45 97 47 99 48 100  49 83 50 99 51 99 52 9953 100  54 77 55 99 56 98 57 99 58 99 59 93 60 99 61 84 62 92 63 99 6499 65 95 66 99 67 100  68 98 69 99 70 99 71 99 72 98 73 99 74 98 75 9776 98 77 98 78 100  79 100  80 98 81 97 82 92 83 99 84 97 85 99 86 96 87100  88 97 89 100  90 98 92 93 93 100  94 100  95 99 96 96 97 100  98 9899 99 100  101  101  99 102  100  103  97 126  57 127  65 128  95 129 87 130  84 131  89 132  98

From the results, it was clarified that the compound of the presentinvention has a PRS inhibitory activity.

Experimental Example 2

The proliferation inhibitory activity of the compound of the presentinvention against human ovarian cancer cell A2780 was evaluated by thefollowing method.

Human ovarian cancer cells A2780 were seeded in a 384 well culture plateat 1000 cells in 30 μL of medium per well by using RPMI-1640 medium(Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serumand penicillin/streptomycin. The next day, 10 μL of RPMI-1640 mediumcontaining the test compound was added to the cells. After 3 days ofculture, 20 μL of CellTiter-Glo Luminescent Cell Viability Assaysolution (Promega, Fitchburg, Wis., US) was added. The luminescencesignal was measured using EnVision (PerkinElmer, Waltham, Mass., US) andthe inhibitory rate (%) of the test compound was calculated with a wellfree of seeding of cell as 100% inhibition.

The proliferation inhibitory rate (%) of A2780 cells by 1 μM testcompound is shown in Table 3.

TABLE 3 Example No. inhibitory rate (%) 20 63 26 92 27 74 29 60 30 99 3597 37 90 38 88 41 72 42 84 44 86 45 76 47 66 48 61 50 78 51 52 52 97 5382 55 67 56 64 57 94 58 75 59 51 60 97 63 88 64 79 65 75 66 80 67 77 6851 70 58 71 69 72 65 74 62 77 63 78 80 79 65 83 58 84 55 85 54 87 74 9061 93 76 94 74 95 70 97 97 98 69 99 70 100  84 101  69 102  89 103  67132  73

From the results, it was clarified that the compound of the presentinvention suppresses proliferation of human ovarian cancer cell A2780.

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) finely divided powder cellulose 10 mg3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablets)

1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets total 140 g

The entire amount of 1), 2) and 3) and 4) (30 g) is kneaded with water,vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and5) (1 g), and the mixture is punched by a tableting machine, whereby1000 tablets containing 30 mg of the compound of Ex. 1 per tablet areobtained.

INDUSTRIAL APPLICABILITY

The compound of the present invention may have a PRS inhibitory actionand may be expected to be useful as a prophylactic or therapeutic agentfor PRS associated diseases and the like including cancer.

This application is based on patent application No. 2016-180749 filed inJapan, the contents of which are encompassed in full herein.

1. A compound represented by the following formula (I):

wherein a group represented by

is an optionally substituted aromatic ring group; R¹ is a hydrogen atom,a halogen atom, a cyano group, an optionally substituted alkyl group, anoptionally substituted cycloalkyl group, an optionally substitutedalkenyl group, an optionally substituted alkynyl group, an optionallysubstituted amino group, or an optionally substituted hydroxy group; X¹is CR² or a nitrogen atom; X² is CR³ or a nitrogen atom; R² and R³ areeach independently a hydrogen atom, a halogen atom, or an optionallysubstituted alkyl group; X³ is CR⁴R⁵ or NR⁶, X⁴ is CR⁷R⁸, X⁵ is CR⁹R¹⁰or an oxygen atom; R⁴ is a hydrogen atom, a cyano group, an optionallysubstituted hydrocarbon group, or an optionally substituted heterocyclicgroup; R⁵ is a cyano group, an optionally substituted hydrocarbon group,or an optionally substituted heterocyclic group; R⁴ and R⁵ areoptionally bonded to each other to form, together with the adjacentcarbon atom, an optionally further substituted ring; and R⁶, R⁷, R⁸, R⁹,and R¹⁰ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group, or an optionally substituted heterocyclicgroup, or a salt thereof.
 2. The compound according to claim 1, whereinthe group represented by

is a C₆₋₁₄ aryl group, a 5- or 6-membered monocyclic aromaticheterocyclic group or a 8 to 14-membered fused polycyclic aromaticheterocyclic group, each of which is optionally substituted by 1 to 5substituents selected from (1) a halogen atom, (2) a cyano group, (3) aC₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms, (4) aC₆₋₁₄ aryl group, (5) a C₁₋₆ alkoxy group and (6) a 5- to 14-memberedaromatic heterocyclic group optionally substituted by 1 to 3substituents selected from (i) a cyano group, (ii) a halogen atom, (iii)a C₁₋₁₂ alkyl group optionally substituted by 1 to 6 substituentsselected from (a) a halogen atom, (b) a cyano group, (c) a hydroxygroup, (d) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3halogen atoms, (e) a C₁₋₆ alkoxy group optionally substituted by a C₁₋₆alkoxy group, (f) a C₆₋₁₄ aryl group, (g) a C₁₋₆ alkoxy-carbonyl group,(h) a carbamoyl group, (i) a C₁₋₆ alkyl-sulfonyl group, (j) a 3- to14-membered non-aromatic heterocyclic group optionally substituted by 1to 3 C₁₋₆ alkyl groups and (k) a 5- to 14-membered aromatic heterocyclicgroup, (iv) a C₃₋₁₀ cycloalkyl group, (v) a 3- to 14-memberednon-aromatic heterocyclic group, (vi) a C₁₋₆ alkoxy-carbonyl and (vii)an oxo group; R¹ is (1) a hydrogen atom, (2) a halogen atom, (3) analkyl group optionally substituted by 1 to 3 substituents selected froma halogen atom, a cyano group, a hydroxy group and a C₁₋₆ alkoxy group,(4) an alkynyl group optionally substituted by a hydroxy group, or (5) ahydroxy group optionally substituted by a C₁₋₆ alkyl group; X¹ isCR^(2a) (R^(2a) is a hydrogen atom or a halogen atom) or a nitrogenatom; X² is CR^(3a) (R^(3a) is a hydrogen atom or a halogen atom) or anitrogen atom; X³ is CR^(4b)R^(5b) (R^(4b) and R^(5b) are eachindependently a cyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group ora C₃₋₁₀ cycloalkyl group); X⁴ is CR^(7b)R^(8b) (R^(7b) and R^(8b) areeach independently (1) a hydrogen atom or (2) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from a cyanogroup, a hydroxy group and a C₁₋₆ alkoxy group); and X⁵ isCR^(9b)R^(10b) (R^(9b) and R^(10b) are each independently a hydrogenatom or a C₁₋₆ alkyl group); or a salt thereof.
 3. A medicamentcomprising the compound according to claim 1 or a salt thereof.
 4. Themedicament according to claim 3 which is a PRS inhibitor.
 5. Themedicament according to claim 3 which is a prophylactic or therapeuticagent for cancer.
 6. The compound according to claim 1 or a salt thereofwhich is used for the prophylaxis or treatment of cancer.
 7. A methodfor inhibiting PRS in a mammal, comprising administering an effectiveamount of the compound according to claim 1 or a salt thereof to themammal.
 8. A method for preventing or treating cancer in a mammal,comprising administering an effective amount of the compound accordingto claim 1 or a salt thereof to the mammal.
 9. Use of the compoundaccording to claim 1 or a salt thereof for producing a prophylactic ortherapeutic agent for cancer.